CLOSTRIDIAL NEUROTOXINS COMPRISING AN ACTIVATING EXOGENOUS PROTEASE CLEAVAGE SITE FIELD OF THE INVENTION The present invention relates to clostridial neurotoxins engineered to comprise an exogenous protease cleavage site within a modified activation loop, wherein cleavage at said site produces an active di-chain clostridial neurotoxin. The invention also relates to methods for manufacturing the same, as well as related pharmaceutical compositions, nucleotide sequences, and therapeutic and cosmetic uses. The invention further relates to a method for proteolytically processing said single-chain clostridial neurotoxins into a corresponding di- chain clostridial neurotoxin. BACKGROUND OF THE INVENTION Bacteria in the genus Clostridia produce highly potent and specific protein toxins, which can poison neurons and other cells to which they are delivered. Examples of such clostridial neurotoxins include the neurotoxins produced by C. tetani (TeNT) and by C. botulinum (BoNT) serotypes A-G, and X (see WO 2018/009903 A2), as well as those produced by C. baratii and C. butyricum. Among the clostridial neurotoxins are some of the most potent toxins known. By way of example, botulinum neurotoxins have median lethal dose (LD50) values for mice ranging from 0.5 to 5 ng/kg, depending on the serotype. Both tetanus and botulinum toxins act by inhibiting the function of affected neurons, specifically the release of neurotransmitters. While botulinum toxin acts at the neuromuscular junction and inhibits cholinergic transmission in the peripheral nervous system, tetanus toxin acts in the central nervous system. Clostridial neurotoxins are expressed as single-chain polypeptides in Clostridium. Each clostridial neurotoxin has a catalytic light chain separated from the heavy chain (encompassing the N-terminal translocation domain and the C-terminal receptor binding domain) by an exposed region called the activation loop. During protein maturation proteolytic cleavage of the activation loop separates the light and heavy chain of the clostridial neurotoxin, which are held together by a disulphide bridge, to create fully active di-chain toxin. This activation process must be reproduced during standard production of recombinant toxin production. Exogenous proteases such as trypsin or Lys-C with well-defined cleavage motifs are used for proteolytically activating single-chain clostridial neurotoxins in conventional production methods. However, for some clostridial neurotoxins, incubation with Lys-C or trypsin results in partial or improper cleavage of the single-chain polypeptide resulting in the production of contaminating single-chain and/or inactive cleavage/degradation products (e.g. in the case of BoNT/E). For instance, for Botulinum neurotoxin serotype X (BoNT/X, see WO 2018/009903 A2), activation is problematic, with cleavage using trypsin or Lys-C completely degrading the polypeptide. Thus, at present there is no universal exogenous protease for activation of clostridial neurotoxins. This is particularly problematic upon identification of a new clostridial neurotoxin or production of a modified (e.g. chimeric or hybrid) neurotoxin, which requires screening of multiple proteases to determine correct activation. For re-targeted clostridial neurotoxins, some standard proteases used for activation can also cleave within the exogenous targeting moieties, resulting in incorrectly processed proteins with reduced targeting to the desired cell type. To avoid such off-target cleavage, either alternative targeting moieties must be identified (which may not always be possible), or the targeting moieties must be designed to remove the cleavage site for the standard protease, which may negatively impact the structure of the targeting moiety, and/or add to design and production costs. Furthermore, in vitro activation of clostridial neurotoxins is associated with numerous disadvantages. There is a cost associated with the use of an exogenous protease (particularly GMP-grade protease), and its removal following activation of the clostridial neurotoxin. Dependence on a single or limited number of suppliers for GMP-grade protease can also create weakness in the supply/production chain. Purification of the activated clostridial neurotoxin from the activating exogenous protease can also affect production efficiency and yield. In addition, production of active di-chain clostridial neurotoxins according to conventional production methods necessitates strict safety and control procedures, also adding to production costs and time. Strict safety precautions are also required for practitioners working with active di-chain clostridial neurotoxins. The present invention overcomes one or more of the above-mentioned problems. SUMMARY OF THE INVENTION The present inventors have previously demonstrated that insertion of a furin cleavage site into the activation loop of a clostridial neurotoxin allows for the in vivo activation of clostridial neurotoxins (see PCT Application No. PCT/GB2022/050756; which is herein incorporated by reference in its entirety), and have also demonstrated that endosomal proteases can be used to cleave clostridial neurotoxins, opening up a new paradigm allowing for both in vivo activation of clostridial neurotoxins, and also the provision of alternative means for in vitro activation. The present inventors have also previously shown that the BoNT/C1 activation loop can be used as a universal activation loop for clostridial neurotoxins (see WO2020/065336; which is herein incorporated by reference in its entirety). However, the use of the BoNT/C1 activation loop can in some circumstances be undesirable. In particular, the native BoNT/C1 activation loop sequence is sensitive to cleavage by Factor Xa, Lys-C, trypsin and enterokinase. Some clostridial neurotoxins are sensitive to off-target cleavage by one or more of these enzymes. Further, there can be costs and difficulties associated with sourcing these proteases at a GMP-compliant grade. Therefore, providing an expanded tool kit of engineered clostridial neurotoxins and activating proteases would offer further benefits in this technical space. In particular, it would be advantageous to provide means to activate clostridial neurotoxins use proteases which are not associated with issues such as (i) sourcing GMP-compliant proteases; (ii) proteases that can work with desirable re-targeted clostridial neurotoxin architectures; (iii) reducing non-specific cleavage and hence undesirable truncation, which requires additional purification and/or impacts on yield; and/or (iv) increasing utility across clostridial neurotoxin serotypes. The present inventors have now surprisingly demonstrated that specific cleavage sites for other exogenous proteases, particularly thrombin, tissue plasminogen activator (t-PA) and urokinase (u-PA) can be introduced into a modified BoNT/C1 activation loop, and that this modified BoNT/C1 activation loop can be used to engineer clostridial neurotoxins, which may then be cleaved and activated by these proteases. Thus, the introduction of one or more exogenous protease cleavage site into a modified BoNT/C activation loop does not disrupt the functioning of the modified BoNT/C activation loop, and that a modified BoNT/C activation loop may still be used as a universal activation loop for clostridial neurotoxins. Furthermore, the present inventors have even more surprisingly shown that clostridial neurotoxins engineered in this manner can be activated by such proteases with improved cleavage and specificity and the potential for reduced off-target protease activity, with the potential to provide improved rates of activation, reduced production of truncation products and allowing lower concentrations of activating protease to be used. Further, such exogenous cleavage sites can potentially be introduced whilst advantageously maintaining the clostridial activation loop architecture. In addition, the exogenous protease-activated engineered clostridial neurotoxins of the invention offer several potential benefits compared with conventionally activated clostridial neurotoxins, such as improving yield and/or reducing manufacturing burden/costs. Accordingly, the invention provides an engineered clostridial neurotoxin, wherein the endogenous activation loop is replaced by a modified BoNT/C activation loop, in which the endogenous activation site of the BoNT/C activation loop, or part thereof, has been replaced by an exogenous protease cleavage site, wherein cleavage at said cleavage site results in the production of an (active) di-chain form of the engineered clostridial neurotoxin. The exogenous protease cleavage site is a cleavage site specific for an exogenous proteases may be selected from: (a) thrombin; (b) tissue plasminogen activator (t-PA); and/or (c) urokinase (u-PA); wherein optionally: (i) the exogenous protease is a human protease; (ii) the exogenous protease is comprised in a drug product; and/or (iii) the exogenous protease is a recombinant human protease. The exogenous protease cleavage site may comprise or consist of: (a) a thrombin consensus sequence of SEQ ID NO: 169 or 170; and/or (b) a uPA and/or t-PA consensus sequence of SEQ ID NOs: 172 or 173. The exogenous protease cleavage site may comprise or consist of one or more of LTPRGVRL (SEQ ID NO: 15), LVPRGS (SEQ ID NO: 16), ENKSLVPRGS (SEQ ID NO: 17), SGRSA (SEQ ID NO: 25), PPFGRSAG (SEQ ID NO: 33), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), KRV (SEQ ID NO: 24), GRI (SEQ ID NO: 44) or PGRVVGG (SEQ ID NO: 50). The exogenous protease cleavage site may be between 3 and 10 amino acids in length, preferably between 3 and 8 amino acids in length. The exogenous protease cleavage site may consist of LTPRGVRL (SEQ ID NO: 15), LVPRGS (SEQ ID NO: 16), ENKSLVPRGS (SEQ ID NO: 17), SGRSA (SEQ ID NO: 25), PPFGRSAG (SEQ ID NO: 33), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), KRV (SEQ ID NO: 24), GRI (SEQ ID NO: 44) or PGRVVGG (SEQ ID NO: 50). The exogenous protease cleavage site may comprise or consist of LTPRGVRL (SEQ ID NO: 15), LVPRGS (SEQ ID NO: 16) or ENKSLVPRGS (SEQ ID NO: 17), preferably LTPRGVRL (SEQ ID NO: 15), and the exogenous protease cleavage site may be specific for thrombin, wherein optionally the exogenous protease cleavage site consists of LTPRGVRL (SEQ ID NO: 15), LVPRGS (SEQ ID NO: 16) or ENKSLVPRGS (SEQ ID NO: 17), preferably LTPRGVRL (SEQ ID NO: 15). The exogenous protease cleavage site may comprise or consist of KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), PPFGRSAG (SEQ ID NO: 33), PGSGRSAG (SEQ ID NO: 26) or PGSGRSASGTTGTG (SEQ ID NO: 27) and the exogenous protease cleavage site may be specific for t-PA and/or u-PA, wherein optionally the exogenous protease cleavage site consists of KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), PPFGRSAG (SEQ ID NO: 33), PGSGRSAG (SEQ ID NO: 26) or PGSGRSASGTTGTG (SEQ ID NO: 27). The endogenous neurotoxin activation loop may be one or more selected from SEQ ID NO: 67 to 90. The exogenous protease cleavage site within the modified BoNT/C activation loop may be the only cleavage site for the exogenous protease within the engineered clostridial neurotoxin; no off-site cleavage may occur on contacting the engineered clostridial neurotoxin with the exogenous protease; and/or no light chain truncation of the engineered clostridial neurotoxin may occur on contacting the engineered clostridial neurotoxin with the exogenous protease. The clostridial neurotoxin may be (a) a Botulinum Neurotoxin (BoNT) serotype A, serotype B, serotype C, serotype D, serotype E, serotype F, serotype G or serotype X, or a Tetanus Neurotoxin (TeNT); or (b) a chimeric BoNT or a hybrid BoNT. The engineered clostridial neurotoxin may be a re-targeted clostridial neurotoxin in which an endogenous H _C or H _CC of a clostridial neurotoxin is replaced by an exogenous targeting moiety (TM). In particularly preferred embodiments the clostridial neurotoxin is BoNT/X. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin which (a) (i) is encoded by a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 154, 156, 158, 160, 162 or 164; or (ii) is encoded by a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease consensus sequence, cleavage site or a modified BoNT/C activation loop as defined in any one of claims 3 to 9; and/or (b) comprises a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs:155, 157, 159, 161163, 165, 166, 167 or 168; and/or (c) comprises a polypeptide sequence having (i) at least 70% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as defined in any one of claims 3 to 9, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 70% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as defined in any one of claims 3 to 9, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The invention also provides a method for proteolytically processing an engineered clostridial neurotoxin of the invention into a corresponding di-chain clostridial neurotoxin, the method comprising contacting the engineered clostridial neurotoxin with an exogenous protease specific for the exogenous protease cleavage site, thereby producing a di-chain clostridial neurotoxin. The invention further provides a di-chain clostridial neurotoxin obtainable said method, wherein optionally (a) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence LVPR, preferably ALVPR, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence GSK or GSY; (b) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence SLVPR, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence GSY; (c) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence LTPR, preferably ALTPR, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence GVR, preferably GVRL; (d) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence PGR, and the N- terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence VVG; (e) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence DKR, preferably AIDKR, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence VLY; (f) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence DKR, preferably AIDK, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence RVLY; (g) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence SGR, preferably PGSGR, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence SA, preferably SAY, SAG or SAS; (h) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence SGR, preferably PGSGR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence TL, preferably TLD or TLDC; or (i) the C-terminus of the clostridial neurotoxin light chain ends with the amino acid sequence FGR, and the N-terminus of the clostridial neurotoxin heavy chain begins with the amino acid sequence SA, preferably SAG. The invention also provides a polynucleotide encoding an engineered clostridial neurotoxin of the invention. The invention further provides an expression vector comprising a polynucleotide of the invention, which is operably linked to a promoter. Said polynucleotide or expression vector may: (a) comprise a nucleotide sequence having (i) at least 70% sequence identity to SEQ ID NO: 154, 156, 158, 160, 162 or 164; or (ii) at least 70% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease consensus sequence, cleavage site or a modified BoNT/C activation loop as defined in any one of claims 3 to 9; (b) encode a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 155, 157, 159, 161163, 165, 166, 167 or 168; and/or (c) encode a polypeptide sequence having (i) at least 70% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as defined in any one of claims 3 to 9, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 70% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as defined in any one of claims 3 to 9, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The invention also provides a method of producing an engineered clostridial neurotoxin of the invention comprising the step of expressing a polynucleotide of the invention or an expression vector of the invention in a cell, and recovering the expressed engineered clostridial neurotoxin. Said method may further comprise a step of introducing a polynucleotide of the invention or an expression vector of the invention into the cell. The invention further provides a cell expressing an engineered clostridial neurotoxin of the invention. Said cell may comprise a polynucleotide of the invention, or an expression vector of the invention. The invention also provides a pharmaceutical composition comprising an engineered clostridial neurotoxin of the invention, or a di-chain clostridial neurotoxin of the invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, propellant and/or salt. The invention further provides an engineered clostridial neurotoxin of the invention, a di-chain clostridial neurotoxin of the invention, or a pharmaceutical composition of the invention, for use in a method of preventing or treating a disease or disorder for which a therapy with a botulinum neurotoxin is indicated, wherein optionally said disease or disorder is selected from a condition associated with unwanted immune secretion, strabismus, blepharospasm, squint, dystonia (e.g. spasmodic dystonia, oromandibular dystonia, focal dystonia, tardive dystonia, laryngeal dystonia, limb dystonia, cervical dystonia), torticollis (e.g. spasmodic torticollis), beauty therapy (cosmetic) applications benefiting from cell/muscle incapacitation (via SNARE down-regulation or inactivation), neuromuscular disorder or condition of ocular motility (e.g. concomitant strabismus, vertical strabismus, lateral rectus palsy, nystagmus, dysthyroid myopathy), writer's cramp, bruxism, Wilson's disease, tremor, tics, segmental myoclonus, spasms, spasticity due to chronic multiple sclerosis, spasticity resulting in abnormal bladder control, animus, back spasm, charley horse, levator pelvic syndrome, spina bifida, tardive dyskinesia, Parkinson's disease, stuttering, hemifacial spasm, eyelid disorder, cerebral palsy, focal spasticity, spasmodic colitis, neurogenic bladder, anismus, limb spasticity, tics, tremors, bruxism, anal fissure, achalasia, dysphagia, lacrimation, hyperhydrosis, excessive salivation, excessive gastrointestinal secretions, muscle pain (e.g. pain from muscle spasms), headache pain (e.g. tension headache or migraine), phantom pain (e.g. phantom limb pain), brow furrows, skin wrinkles, cancer, uterine disorders, uro-genital disorders, urogenital-neurological disorders, bladder pain syndrome, interstitial cystitis, chronic neurogenic inflammation, and a smooth muscle disorder. Preferably, a composition of the invention may be used in the prevention or treatment of a disease or condition selected from: limb spasticity (upper or lower); cervical dystonia; headache disorders (preferably migraine); blepharospasm; hemifacial spasm; and lower urinary tract disorders (e.g. bladder pain syndrome (preferably interstitial cystitis); overactive bladder; and detrusor overactivity (e.g. neurogenic detrusor overactivity. The invention also provides the use of an engineered clostridial neurotoxin of the invention, a di-chain clostridial neurotoxin of the invention, or a pharmaceutical composition of the invention, in the manufacture of a medicament for preventing or treating a disease or disorder for which a therapy with a botulinum neurotoxin is indicated, wherein optionally said disease or disorder is selected from a condition associated with unwanted immune secretion, strabismus, blepharospasm, squint, dystonia (e.g. spasmodic dystonia, oromandibular dystonia, focal dystonia, tardive dystonia, laryngeal dystonia, limb dystonia, cervical dystonia), torticollis (e.g. spasmodic torticollis), beauty therapy (cosmetic) applications benefiting from cell/muscle incapacitation (via SNARE down-regulation or inactivation), neuromuscular disorder or condition of ocular motility (e.g. concomitant strabismus, vertical strabismus, lateral rectus palsy, nystagmus, dysthyroid myopathy), writer's cramp, bruxism, Wilson's disease, tremor, tics, segmental myoclonus, spasms, spasticity due to chronic multiple sclerosis, spasticity resulting in abnormal bladder control, animus, back spasm, charley horse, levator pelvic syndrome, spina bifida, tardive dyskinesia, Parkinson's disease, stuttering, hemifacial spasm, eyelid disorder, cerebral palsy, focal spasticity, spasmodic colitis, neurogenic bladder, anismus, limb spasticity, tics, tremors, bruxism, anal fissure, achalasia, dysphagia, lacrimation, hyperhydrosis, excessive salivation, excessive gastrointestinal secretions, muscle pain (e.g. pain from muscle spasms), headache pain (e.g. tension headache or migraine), phantom pain (e.g. phantom limb pain), brow furrows, skin wrinkles, cancer, uterine disorders, uro-genital disorders, urogenital-neurological disorders, bladder pain syndrome, interstitial cystitis, chronic neurogenic inflammation, and a smooth muscle disorder. Preferably, a composition of the invention may be used in the prevention or treatment of a disease or condition selected from: limb spasticity (upper or lower); cervical dystonia; headache disorders (preferably migraine); blepharospasm; hemifacial spasm; and lower urinary tract disorders (e.g. bladder pain syndrome (preferably interstitial cystitis); overactive bladder; and detrusor overactivity (e.g. neurogenic detrusor overactivity. In such therapies, the clostridial neurotoxin may be administered to a subject in single- chain form. The clostridial neurotoxin or pharmaceutical composition may be substantially free of a di-chain form of the clostridial neurotoxin. The clostridial neurotoxin or pharmaceutical composition may comprise less than 400 pg di-chain clostridial neurotoxin per 100 ng single- chain clostridial neurotoxin, or less than 300 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 200 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 100 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 50 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin. Alternatively in such therapies, the clostridial neurotoxin may be administered to a subject in di-chain form. The clostridial neurotoxin or pharmaceutical composition may be substantially free of a single-chain form of the clostridial neurotoxin. The clostridial neurotoxin or pharmaceutical composition may comprise less than 400 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 300 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 200 pg single- chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 100 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 50 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin. The invention also provides a cosmetic composition comprising an engineered clostridial neurotoxin of the invention, or a di-chain clostridial neurotoxin of the invention, and a cosmetically acceptable carrier, excipient, diluent, adjuvant, propellant and/or salt. The invention further provides the use of a cosmetic composition of the invention, for preventing or alleviating a cosmetic indication for which the application of a botulinum neurotoxin is indicated. In such cosmetic indications, the clostridial neurotoxin may be for administration to a subject in single-chain form. The clostridial neurotoxin or cosmetic composition maybe substantially free of a di-chain form of the clostridial neurotoxin. The clostridial neurotoxin or cosmetic composition may comprise less than 400 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 300 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 200 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 100 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin, or less than 50 pg di-chain clostridial neurotoxin per 100 ng single-chain clostridial neurotoxin. Alternatively in such cosmetic indications, the clostridial neurotoxin may be for administration to a subject in single-chain form. The clostridial neurotoxin or cosmetic composition may be substantially free of a single-chain form of the clostridial neurotoxin. The clostridial neurotoxin or cosmetic composition may comprise less than 400 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 300 pg single- chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 200 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 100 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin, or less than 50 pg single-chain clostridial neurotoxin per 100 ng di-chain clostridial neurotoxin. The invention also provides a method for proteolytically processing a single-chain clostridial neurotoxin into a corresponding di-chain clostridial neurotoxin, the method comprising: (a) providing a single-chain clostridial neurotoxin; and (b) contacting the single- chain clostridial neurotoxin with an exogenous protease; wherein the single-chain clostridial neurotoxin has exogenous protease cleavage site and/or modified BoNT/C activation loop as defined herein, and wherein the exogenous protease hydrolyses a peptide bond of the exogenous protease cleavage site and/or modified BoNT/C activation loop, thereby producing a di-chain clostridial neurotoxin, wherein optionally the exogenous protease is selected from thrombin, t-PA, u-PA, FIX and FVIIa. The single-chain clostridial neurotoxin may be: (a) an engineered clostridial neurotoxin of the invention; (b) encoded by a nucleic acid sequence comprising or consisting of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 154, 156, 158, 160, 162 or 164; or (ii) at least 70% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease consensus sequence, cleavage site or a modified BoNT/C activation loop of the invention; (c) comprise or consist of a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 155, 157, 159, 161163, 165, 166, 167 or 168; and/or (d) comprise or consist of a polypeptide sequence having (i) at least 70% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop of the invention, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 70% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop of the invention, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: SDS PAGE gels (+/- DTT) A4952 cleavage by different concentrations of u-PA over time. Figure 2: SDS PAGE gels (+/- DTT) A4953 cleavage by different concentrations of FIX over time. Figure 3: A SDS PAGE gels (+/- DTT) A4954 cleavage by different concentrations of thrombin over time. B Mass spectrogram of A4954 cleaved by thrombin. C SDS PAGE gel showing thrombin can cleave the PGR cleavage site without truncation. Figure 4: A SDS PAGE gel (-/+DTT) showing cleavage of engineered BoNT with an ENKSLVPRGS modified C-loop with thrombin or engineered BoNT with an SGRSA modified C-loop with u-PA or 2 t-PA variants (full-length (t-PA _fl ) and a functional fragment (t-PA _frag )) after 2 hours. Lane 1 = ENKSLVPRGS loop negative control; Lane 2 = SGRSA loop negative control; Lane 3 = ENKSLVPRGS loop with 0.39µg thrombin; Lane 4 = ENKSLVPRGS loop with 1.95µg thrombin; Lane 5 = ENKSLVPRGS loop with 3.90µg thrombin; Lane 6 = SGRSA loop with 0.39µg u-PA; Lane 7 = SGRSA loop with 1.95µg u-PA; Lane 8 = SGRSA loop with 3.90µg u-PA; Lane 9 = SGRSA loop with 0.39µg t-PA _fl ; Lane 10 = SGRSA loop with 1.95µg t- PA _fl ; Lane 11 = SGRSA loop with 3.90µg t-PA _fl ; Lane 12 = SGRSA loop with 0.39µg t-PA _frag ; Lane 13 = SGRSA loop with 1.95µg t-PA _frag ; Lane 14 = SGRSA loop with 3.90µg t-PA _frag . B Mass spectrogram of A5045 cleaved by u-PA. Figure 5: A SDS PAGE gels (-/+DTT) showing cleavage of engineered BoNT with an LTPRGVRL modified C-loop with increasing concentrations of thrombin after 2 hours (top) or 20 hours (bottom). Possible truncation products indicated with black arrow. B SDS PAGE gels (-/+DTT) showing cleavage of engineered BoNT with a PGSGRSAG modified C-loop with increasing concentrations of u-PA, t-PA _fl or t-PA _frag after 2 hours (left), 4 hours (middle) or 20 hours (right). Lanes 1-9 are engineered BoNT with a PGSGRSAG modified C-loop, lane 10 is a comparator lane with engineered BoNT with a SGRSA modified C-loop. Possible truncation products indicated with black arrow. C SDS PAGE gels (-/+DTT) showing cleavage of engineered BoNT with a PGSGRSASGTTGTG modified C-loop with increasing concentrations of u-PA, t-PAfrag or t-PAfl after 2 hours (left), 4 hours (middle) or 20 hours (right). Possible truncation products indicated with black arrow. D SDS PAGE gels (-/+DTT) showing cleavage of engineered BoNT with a PPFGRSAG modified C-loop with increasing concentrations of u-PA, t-PAfrag or t-PAfl after 2 hours (left), 4 hours (middle) or 20 hours (right). Reteplase is visible in some gels (black arrow). E SDS PAGE gels (-/+DTT) showing cleavage of engineered BoNT with a PPFGRSAG modified C-loop with increasing concentrations of t- PAfrag or t-PAfl after 2 hours (left), 4 hours (middle) or 20 hours (right). t-PAfrag (black arrow) and t-PAfl (dotted arrow) are visible in some gels. DETAILED DESCRIPTION OF THE INVENTION Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Singleton, et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 20 ED., John Wiley and Sons, New York (1994), and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY, Harper Perennial, NY (1991) provide the skilled person with a general dictionary of many of the terms used in this disclosure. The meaning and scope of the terms should be clear; however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. In particular, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of this disclosure. The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. Moreover, due to biological functional equivalency considerations, some changes can be made in protein structure without affecting the biological or chemical action in kind or amount. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims. Unless otherwise indicated, any nucleic acid sequences are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively. The headings provided herein are not limitations of the various aspects or embodiments of this disclosure. As used herein, the term "capable of' when used with a verb, encompasses or means the action of the corresponding verb. For example, "capable of interacting" also means interacting, "capable of cleaving" also means cleaves, "capable of binding" also means binds and "capable of specifically targeting…" also means specifically targets. Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within this disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within this disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in this disclosure. Amino acids are referred to herein using the name of the amino acid, the three-letter abbreviation or the single letter abbreviation. The term “protein", as used herein, includes proteins, polypeptides, and peptides. As used herein, the term “amino acid sequence” is synonymous with the term “polypeptide” and/or the term “protein”. In some instances, the term “amino acid sequence” is synonymous with the term “peptide”. In some instances, the term “amino acid sequence” is synonymous with the term “enzyme”. The terms "protein" and "polypeptide" are used interchangeably herein. In the present disclosure and claims, the conventional one-letter and three-letter codes for amino acid residues may be used. The 3- letter code for amino acids as defined in conformity with the IUPACIUB Joint Commission on Biochemical Nomenclature (JCBN). It is also understood that a polypeptide may be coded for by more than one nucleotide sequence due to the degeneracy of the genetic code. A “fragment” of a polypeptide typically comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% or more of the original polypeptide. As used herein, the terms “polynucleotides”, "nucleic acid" and "nucleic acid sequence" refers to any molecule, preferably a polymeric molecule, incorporating units of ribonucleic acid, deoxyribonucleic acid or an analogue thereof. The nucleic acid can be either single-stranded or double-stranded. A single-stranded nucleic acid can be one nucleic acid strand of a denatured double- stranded DNA Alternatively, it can be a single-stranded nucleic acid not derived from any double-stranded DNA. In one aspect, the nucleic acid can be DNA. In another aspect, the nucleic acid can be RNA Suitable nucleic acid molecules are DNA, including genomic DNA or cDNA. Other suitable nucleic acid molecules are RNA, including siRNA, shRNA, and antisense oligonucleotides. As used herein, the term “spacer” refers to a flexible peptide used in an exogenous activation loop or modified BoNT/C activation loop, or with an exogenous protease cleavage site which typically is included to preserve the secondary structure of the exogenous/ modified BoNT/C activation loop within an engineered clostridial neurotoxin of the invention. A spacer for use in an engineered clostridial neurotoxin of the invention may comprise an amino acid sequence of from 1 to 30 amino acid residues, e.g. from 5 to 30 amino acid residues, from 10 to 25 amino acid residues or about 5 to about 20 amino acid residues. A spacer may comprise or consist of small amino acid residues, such as glycine, threonine, arginine, serine, asparagine, glutamine, alanine, aspartic acid, proline, glutamic acid, lysine, leucine and/or valine, particularly glycine, serine, alanine, leucine and/or valine. Spacers comprising or consisting of glycine, serine and/or alanine may be preferred, with glycine and serine being particularly preferred. Accordingly, the most commonly used spacers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker), which comprise a sequence of (Gly-Gly-Gly-Gly-Ser) _n (SEQ ID NO: 137). Non-limiting examples of GS linkers include GS5 or (GGGGS) ₁ (SEQ ID NO: 138); GS10 or (GGGGS) ₂ (SEQ ID NO: 139); GS15 or (GGGGS) ₃ (SEQ ID NO: 140); GS20 or (GGGGS) ₄ (SEQ ID NO: 141); and GS25 or(GGGGS) ₅ (SEQ ID NO: 142). The terms "increased", "increase", "enhance", or "activate" are all used herein to mean an increase by a statically significant amount. The terms "increased", "increase", "enhance", or "activate" can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. The terms "decrease", "reduced", "reduction", or "inhibit" are all used herein to mean a decrease by a statistically significant amount. The terms "reduce," "reduction" or "decrease" or "inhibit" typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, "reduction" or "inhibition" encompasses a complete inhibition or reduction as compared to a reference level. "Complete inhibition" is a 100% inhibition (i.e. abrogation) as compared to a reference level. Other definitions of terms may appear throughout the specification. Before the exemplary embodiments are described in more detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be defined only by the appended claims. It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a clostridial neurotoxin” includes a plurality of such candidate agents and reference to “the clostridial neurotoxin” includes reference to one or more clostridial neurotoxins and equivalents thereof known to those skilled in the art, and so forth. Furthermore, the use of the term "including", as well as other forms, such as "includes" and "included", is not limiting. “About” may generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. Preferably, the term “about” shall be understood herein as plus or minus (±) 5%, preferably ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, of the numerical value of the number with which it is being used. The term "consisting of'' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the invention. As used herein the term "consisting essentially of'' refers to those elements required for a given invention. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that invention (i.e. inactive or non- immunogenic ingredients). Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of” and/or “consisting essentially of” such features. The term “deletion” as used herein refers to removal of one or more amino acid residues of a polypeptide without replacement of one or more amino acid residues at the site of deletion. Thus, where one amino acid residue has been deleted from a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide has x-1 amino acid residues. The term “indel” as used herein refers to deletion of one or more amino acid residues of a polypeptide and insertion at the deletion site of a different number of amino acid residues (either greater or fewer amino acid residues) when compared to the number of amino acid residues deleted. Thus, for an indel where two amino acid residues have been deleted from a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide has x-1 amino acid residues or x+≥1 amino acid residues. The insertion and deletion can be carried out in any order, sequentially or simultaneously. The term “substitution” as used herein refers to replacement of one or more amino acid residues with the same number of amino acid residues at the same site. Thus, for a substitution of a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide also has x amino acid residues. Preferably a substitution is a substitution at a single amino acid position. The term “insertion” as used herein refers to addition of one or more amino acid residues of a polypeptide without deletion of one or more amino acid residues of the polypeptide at the site of insertion. Thus, where one amino acid residue has been inserted into a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide has x+1 amino acid residues. The term “deletion” as used herein refers to removal of one or more amino acid residues of a polypeptide without replacement of one or more amino acid residues at the site of deletion. Thus, where one amino acid residue has been deleted from a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide has x-1 amino acid residues. The term “indel” as used herein refers to deletion of one or more amino acid residues of a polypeptide and insertion at the deletion site of a different number of amino acid residues (either greater or fewer amino acid residues) when compared to the number of amino acid residues deleted. Thus, for an indel where two amino acid residues have been deleted from a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide has x-1 amino acid residues or x+≥1 amino acid residues. The insertion and deletion can be carried out in any order, sequentially or simultaneously. The term “substitution” as used herein refers to replacement of one or more amino acid residues with the same number of amino acid residues at the same site. Thus, for a substitution of a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide also has x amino acid residues. Preferably a substitution is a substitution at a single amino acid position. The term “insertion” as used herein refers to addition of one or more amino acid residues of a polypeptide without deletion of one or more amino acid residues of the polypeptide at the site of insertion. Thus, where one amino acid residue has been inserted into a polypeptide sequence having x number of amino acid residues (for example), the resultant polypeptide has x+1 amino acid residues. Concentrations, amounts, volumes, percentages and other numerical values may be presented herein in a range format. It is also to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. An individual can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications related to such a condition, and optionally, have already undergone treatment for a condition as defined herein or the one or more complications related to said condition. Alternatively, an individual can also be one who has not been previously diagnosed as having a condition as defined herein or one or more complications related to said condition. For example, an individual can be one who exhibits one or more risk factors for a condition, or one or more complications related to said condition or a subject who does not exhibit risk factors. An "individual in need" of treatment for a particular condition can be an individual having that condition, diagnosed as having that condition, or at risk of developing that condition. The terms “subject”, “individual” and “patient” are used interchangeably herein to refer to a mammalian individual. An “individual” may be any mammal. Generally, the individual may be human; in other words, in one embodiment, the “individual” is a human. A “individual” may be an adult, juvenile or infant. An “individual” may be male or female. The term “pharmaceutically acceptable” as used herein means approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized pharmacopeia. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that such publications constitute prior art to the claims appended hereto. Engineered Clostridial Neurotoxins The present invention provides an engineered clostridial neurotoxin, comprising a exogenous protease cleavage site. Typically cleavage at said exogenous protease cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. In other words, cleavage at the exogenous protease cleavage site results in activation of an engineered clostridial neurotoxin. Typically according to the invention, an engineered clostridial neurotoxin lacks the endogenous activation loop (or a part thereof) of the pre-engineering clostridial neurotoxin from which the engineered neurotoxin is derived. The term “endogenous activation loop” is as described herein. In these engineered clostridial neurotoxins of the invention, the endogenous activation loop (or a part thereof) of the pre-engineering clostridial neurotoxin is replaced by a modified BoNT/C activation loop, particularly a modified BoNT/C1 activation loop. The endogenous BoNT/C1 activation loop has a consensus sequence of Cyst-(Xaa)a- Ile-Asp/Glu-Gly-Arg-(Yaa)b-Cys (SEQ ID NO: 1), wherein a = 1-10 and b = 4-15, typically wherein a = 2-4 and/or b=6-10, preferably where a=3 and/or b=8. Specific BoNT/C1 activation loops comprise or consist of CHKAIDGRSLYNKTLDC (SEQ ID NO: 2) or CHKAIEGRSLYNKTLDC (SEQ ID NO: 3). Within the endogenous BoNT/C1 activation loop, enterokinase and Factor Xa are both capable of cleaving immediately C-terminal to the IDGR or IEGR sequence, and the presence of lysine and arginine residues allows cleavage by trypsin and Lys-C. In a modified BoNT/C activation loop of the invention, one or more of these endogenous activation sites within the endogenous activation loop have been replaced by one or more exogenous protease cleavage site. Typically a modified BoNT/C activation loop of the invention lacks a Factor Xa/enterokinase cleavage site, such that the modified BoNT/C activation loop is not sensitive to cleavage by Factor Xa and/or enterokinase. Thus, a modified BoNT/C (BoNT/C1) activation loop of the invention may lack an IDGR or IEGR sequence. Further, a modified BoNT/C (BoNT/C1) activation loop of the invention typically comprises one or more exogenous protease cleavage site. In other words, a modified BoNT/C (BoNT/C1) activation loop may have the endogenous BoNT/C activation site, or part thereof, replaced by one or more exogenous protease cleavage site, as described herein. Thus, the invention provides an engineered clostridial neurotoxin, in which the endogenous activation loop is replaced by a modified BoNT/C (BoNT/C1) activation loop, in which the endogenous activation site of the BoNT/C (BoNT/C1) activation loop, or part thereof, has been replaced by one or more exogenous protease cleavage site, and wherein cleavage at said cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. A modified BoNT/C (BoNT/C1) activation loop according to the invention may begin with the N-terminal residues CHKA (SEQ ID NO: 4), such as CHKAI (SEQ ID NO: 5) or CHKAID (SEQ ID NO: 6). Typically, such modified BoNT/C (BoNT/C1) activation loops lack an IDGR (SEQ ID NO: 7) or IEGR (SEQ ID NO: 8) sequence, such that the sequence of the modified BoNT/C (BoNT/C1) activation loop does not comprise the sequence CHKAIDGR (SEQ ID NO: 9) or CHKAIEGR (SEQ ID NO: 10) at the N-terminus. Alternatively or additionally, modified BoNT/C (BoNT/C1) activation loop according to the invention may end with the C- terminal residues TLDC (SEQ ID NO: 11), such as KTLDC (SEQ ID NO: 12), YNKTLDC (SEQ ID NO: 13) or LYNKTLDC (SEQ ID NO: 14). A modified BoNT/C (BoNT/C1) activation loop according to the invention may be between about 10 to about 30 (e.g.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) amino acids in length, such as between about 15 to about 25 (e.g.15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25) amino acids in length, preferably between about 17 to about 24 (e.g. 17, 18, 19, 20, 21, 22, 23 or 24) amino acids in length. Particularly preferred are modified BoNT/C (BoNT/C1) activation loops which are 17 amino acids in length, as such modified BoNT/C (BoNT/C1) activation loops are the same length as the endogenous BoNT/C (BoNT/C1) activation loop. A modified BoNT/C (BoNT/C1) activation loop may comprise one or more exogenous protease cleavage site of LTPRGVRL (SEQ ID NO: 15), ENKSLVPRGS (SEQ ID NO: 17), LVPRGS (SEQ ID NO: 16), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), PPFGRSAG (SEQ ID NO: 33), VVPRVELVA (SEQ ID NO: 32), or GRI (SEQ ID NO: 44) into the endogenous activation loop of the clostridial neurotoxin, wherein cleavage at said cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. In particular, a modified BoNT/C (BoNT/C1) activation loop may comprise one or more exogenous protease cleavage site of LTPRGVRL (SEQ ID NO: 15), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), VVPRVELVA (SEQ ID NO: 32), PPFGRSAG (SEQ ID NO: 33) or GRI (SEQ ID NO: 44), preferably LTPRGVRL (SEQ ID NO: 15), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25) or PPFGRSAG (SEQ ID NO: 33). A modified BoNT/C (BoNT/C1) activation loop may comprise one or more exogenous protease cleavage site of LTPRGVRL (SEQ ID NO: 15), ENKSLVPRGS (SEQ ID NO: 17), SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), or PPFGRSAG (SEQ ID NO: 33). The invention also provides an engineered clostridial neurotoxin, comprising an exogenous protease cleavage site formed by introducing one or more amino acid sequence comprising or consisting of LTPRGVRL (SEQ ID NO: 15), ENKSLVPRGS (SEQ ID NO: 17), LVPRGS (SEQ ID NO: 16), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), PPFGRSAG (SEQ ID NO: 33), VVPRVELVA (SEQ ID NO: 32), or GRI (SEQ ID NO: 44) into the endogenous activation loop of the clostridial neurotoxin, wherein cleavage at said cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. In particular, the one or more amino acid sequence may comprise or consist of LTPRGVRL (SEQ ID NO: 15), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), VVPRVELVA (SEQ ID NO: 32), PPFGRSAG (SEQ ID NO: 33) or GRI (SEQ ID NO: 44), preferably LTPRGVRL (SEQ ID NO: 15), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25) or PPFGRSAG (SEQ ID NO: 33). The invention provides an engineered clostridial neurotoxin, comprising an exogenous protease cleavage site formed by introducing one or more amino acid sequence comprising or consisting of LTPRGVRL (SEQ ID NO: 15), ENKSLVPRGS (SEQ ID NO: 17), SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), or PPFGRSAG (SEQ ID NO: 33) into the endogenous activation loop of the clostridial neurotoxin, wherein cleavage at said cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. The endogenous (native) activation loop of a clostridial neurotoxin may be replaced (or partially replaced) by said exogenous protease cleavage site. Thus, an engineered clostridial neurotoxin of the invention may comprise an exogenous activation loop. The term “exogenous protease cleavage site” may be used interchangeably with the term “exogenous protease activation site”. An exogenous activation loop as defined herein will typically comprise or consist of one or more exogenous protease cleavage site. The engineered clostridial neurotoxins of the invention, whether comprising one or more exogenous protease cleavage site within a modified BoNT/C (BoNT/C1) activation loop or within an exogenous activation loop, may be activated in vivo. Thus, the engineered clostridial neurotoxins open up a new field of processing and therapeutic use for clostridial neurotoxins, enabling toxins to be produced and administered as single-chain clostridial neurotoxins, which are then cleaved to produce the active di-chain form in vivo. The engineered clostridial neurotoxins of the invention, whether comprising one or more exogenous protease cleavage site within a modified BoNT/C (BoNT/C1) activation loop or within an exogenous activation loop, may be activated in vitro. The introduction of an exogenous protease cleavage site, whether comprising one or more exogenous protease cleavage site within a modified BoNT/C (BoNT/C1) activation loop or within an exogenous activation loop, into an engineered clostridial neurotoxin of the invention typically provides advantages in the manufacturing and/or processing of engineered clostridial neurotoxins of the invention, such as (i) sourcing GMP-compliant proteases; (ii) proteases that can work with desirable re-targeted clostridial neurotoxin architectures; (iii) reducing non-specific cleavage and hence undesirable truncation, which requires additional purification and/or impacts on yield; (iv) increasing utility across clostridial neurotoxin serotypes, or any combination thereof, as described herein; and/or (v) improving the overall rate of activation, which has the potential to enable the production of activated di-chain compositions, reducing the amount of protease required and/or reducing the complexity/number of steps during purification. The clostridial neurotoxin (pre-engineering) is typically characterised in that the endogenous activation loop is inefficiently proteolytically processed by one or more exogenous protease. In contrast to the clostridial neurotoxin (pre-engineering), an engineered clostridial neurotoxin of the invention is not inefficiently proteolytically processed by the one or more exogenous protease for which a cleavage site has been introduced and/or a peptide bond outside of the exogenous activation loop of the engineered clostridial neurotoxin is not hydrolysed by said one or more exogenous protease. Thus, the clostridial neurotoxin (pre- engineering) is typically resistant to proteolytic processing by one or more exogenous protease. The terms “inefficiently proteolytically processed by one or more exogenous protease”, “resistant to proteolytic processing by one or more exogenous protease”, “not substantially hydrolysed by one or more exogenous protease” “inefficiently activated by one or more exogenous protease”, “resistant to activation by one or more exogenous protease” and “not substantially activated by one or more exogenous protease” are used interchangeably herein. Typically, the clostridial neurotoxin (pre-engineering) is typically resistant to proteolytic processing by the one or more exogenous protease for which cleavage site(s) have been introduced according to the present invention. The clostridial neurotoxin (pre-engineering) may further be resistant to proteolytic processing by one or more exogenous protease for which cleavage site(s) have not been introduced according to the invention. A clostridial neurotoxin (pre-engineering) is typically one in which a peptide bond (either within or outside of the activation loop) is not, or is not substantially, hydrolysed by one or more exogenous protease. The term “not substantially hydrolysed” means that less than 10%, 5%, 4%, 3%, 2% or 1% of the clostridial neurotoxin present in a reaction contains a peptide bond that has been hydrolysed by one or more exogenous protease in a method of the invention. Accordingly, a clostridial neurotoxin (pre-engineering) typically does not contain one or more exogenous protease consensus sequence (e.g. any one or more of SEQ ID NOs: 169, 170, 172 or 173) and/or one or more exogenous protease cleavage site (e.g. as defined herein, such as any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly any one of SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably any one of SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32) within its endogenous activation loop. A clostridial neurotoxin (pre-engineering) may not contain one or more exogenous protease consensus sequence (e.g. any one or more of SEQ ID NOs: 169, 170, 172 or 173) and/or one or more exogenous protease cleavage site (e.g. as defined herein, such as any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly any one of SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably any one of SEQ ID NOs: 15, 17, 16, 25, 26, 27, 24, 33 and/or 32, for an exogenous protease that is intended for use in activating an engineered clostridial neurotoxin. By way of non-limiting example, if an engineered clostridial neurotoxin contains a thrombin cleavage site, then the corresponding pre-engineering clostridial neurotoxin may not comprise a thrombin cleavage site within its endogenous activation loop. The invention may comprise replacing an endogenous activation loop (or part thereof) of any clostridial neurotoxin with a modified BoNT/C activation loop (or part thereof) comprising one or more exogenous protease cleavage site as described herein. The invention may comprise replacing an endogenous activation loop (or part thereof) of any clostridial neurotoxin with one or more exogenous protease cleavage site or an exogenous activation loop comprising one or more exogenous protease cleavage site as described herein. The clostridial neurotoxin may be a botulinum neurotoxin (BoNT) or a tetanus neurotoxin (TeNT). Preferably the clostridial neurotoxin is a botulinum neurotoxin, such as BoNT/A, BoNT/B, BoNT/C1, BoNT/D, BoNT/E, BoNT/F, BoNT/G or BoNT/X, or a chimeric or hybrid thereof. In some particularly preferred embodiments the clostridial neurotoxin is BoNT/X or a chimera or hybrid thereof. The term “endogenous activation loop” as used herein means an activation loop present in a subject clostridial neurotoxin, e.g. a subject clostridial neurotoxin of the indicated serotype. For example, BoNT/A1 includes a BoNT/A1 heavy chain and light chain, thus the endogenous activation loop of BoNT/A1 is an A1 activation loop. For clostridial neurotoxin chimeras or hybrids, the person skilled in the art can identify the “endogenous activation loop”, for example by determining the serotype(s) from which the L-chain and H _N domain are derived. In some embodiments, a chimera or hybrid clostridial neurotoxin may have an endogenous activation loop that is a fusion of an activation loop from two different serotypes. By way of example, a chimeric clostridial neurotoxin such as BoNT/A1C ₁ has a BoNT/A ₁ light chain and translocation domain, thus the endogenous BoNT/A1C1 activation loop is an A1 activation loop. The endogenous activation loop, is typically bounded by cysteine residues that form a disulphide bridge and covalently link the light and heavy chains of a (pre-engineering) clostridial neurotoxin. Thus, an endogenous activation loop sequence may be recited including the bounding cysteine residues (as described herein), or without the bounding cysteine residues. One of ordinary skill in the art would understand that the definitions may be used interchangeably, and would readily be able to identify an endogenous activation loop, either including or excluding the bounding cysteine residues. Typically an “endogenous activation loop” is any activation loop that is does not comprise or consist of one or more exogenous protease consensus sequence (e.g. any one or more of SEQ ID NOs: 169, 170, 172 or 173) and/or one or more exogenous protease cleavage sites as described herein (e.g. SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50- 52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 25, 26, 27, 24, 33 and/or 32, more preferably , SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33). By contrast, an “exogenous activation loop” as used herein means an activation loop that is different to the endogenous activation loop present in a subject clostridial neurotoxin, e.g., a subject clostridial neurotoxin of the indicated serotype, and wherein the exogenous activation loop comprises one or more exogenous protease cleavage site. For example, a BoNT/A activation loop has a different polypeptide sequence to a wild-type BoNT/X activation loop, therefore the BoNT/A activation loop is exogenous to BoNT/X. By way of further example, a BoNT/C1 activation loop has a different polypeptide sequence to a wild-type BoNT/A1 activation loop, therefore the BoNT/C1 activation loop is exogenous to BoNT/A1. Thus, the term “exogenous activation loop” as used herein may refer to a modified BoNT/C (BoNT/C1) activation loop of the invention unless expressly stated otherwise. For clostridial neurotoxin chimeras or hybrids, the person skilled in the art can determine whether an activation loop is an “exogenous activation loop”, for example by determining the serotype(s) from which the L-chain and HN domain are derived. For example, where the L-chain is a BoNT/B L-chain and the HN domain is from BoNT/D, the endogenous activation loop may have a portion of a BoNT/B sequence and a portion of a BoNT/D sequence, and if an activation loop (e.g. a C1 activation loop) is different thereto, and comprises one or more exogenous protease cleavage site, it is considered an “exogenous activation loop”. Determination of whether an activation loop is an “endogenous activation loop” may be made by aligning the sequence of a subject clostridial neurotoxin with the activation loop, and seeing if the activation loop is present in the subject clostridial neurotoxin sequence. If it is present, then the activation loop can be identified as an endogenous activation loop. As described herein, the endogenous activation loop of a clostridial neurotoxin is replaced by an exogenous cleavage site which is one or more exogenous protease cleavage site, by an exogenous activation loop which comprises one or more exogenous protease cleavage site, or by a modified BoNT/C (BoNT/C1) activation loop in which the endogenous BoNT/C (BoNT/C1) activation site (or part thereof) has been replaced by one or more exogenous protease cleavage site. According to the invention, one or more exogenous protease cleavage site may be inserted between the two cysteine residues that bound the endogenous activation loop of a pre-engineering clostridial neurotoxin, although the precise position of the one or more exogenous protease cleavage site within the endogenous activation loop is not limited, provided that the conformation of the resultant engineered clostridial neurotoxin is not disrupted and/or the engineered clostridial neurotoxin rendered non-functional. In a modified BoNT/C (BoNT/C1) activation loop of the invention, the one or more exogenous protease cleavage site may be inserted between the two cysteine residues that bound the endogenous BoNT/C (BoNT/C1) activation loop. The entire endogenous activation loop may be replaced by one or more exogenous protease cleavage site or an exogenous activation loop comprising one or more exogenous protease cleavage site as described herein. Alternatively, a part or portion of the endogenous activation loop may be replaced (also referred to herein as partial replacement of the endogenous activation loop), such as at least 5, 10, 15, 20, 25, 30, 35 or 40 amino acid residues of the endogenous activation loop are replaced. Preferably 5 to 20, more preferably 5 to 15 amino acid residues of the endogenous activation loop are replaced. Typically partial replacement involves the replacement of consecutive amino acids within the endogenous activation loop. Thus, in partial replacement of the endogenous activation loop, at least one amino acid residue of the endogenous activation loop is retained. Preferably between about 5 to about 15 (e.g.5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15), such as between about 5 to about 12 (e.g.5, 6, 7, 8, 9, 10, 11 or 12) of the (e.g.5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) of the endogenous activation loop is retained. The retained amino acids residues may be at the N- terminal and/or C-terminal of the endogenous activation loop. The entire (unmodified) BoNT/C (BoNT/C1) activation loop may be replaced by one or more exogenous protease cleavage site as described herein. Preferably, a part or portion of the (unmodified) BoNT/C (BoNT/C1) activation loop may be replaced (also referred to herein as partial replacement of the (unmodified) BoNT/C (BoNT/C1) activation loop), such as at least 5, 10, 11, 12, 13, 14, 15, 16 or 17 amino acid residues of the (unmodified) BoNT/C (BoNT/C1) activation loop are replaced. Preferably 3 to 15, more preferably 5 to 10 amino acid residues of the (unmodified) BoNT/C (BoNT/C1) activation loop are replaced. Typically partial replacement involves the replacement of consecutive amino acids within the (unmodified) BoNT/C (BoNT/C1) activation loop. Thus, in partial replacement of the (unmodified) BoNT/C (BoNT/C1) activation loop, at least one amino acid residue of the (unmodified) BoNT/C (BoNT/C1) activation loop is retained. Preferably between about 5 to about 15 (e.g.5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15), such as between about 5 to about 12 (e.g.5, 6, 7, 8, 9, 10, 11 or 12) of the (e.g.5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) of the (unmodified) BoNT/C (BoNT/C1) activation loop is retained. The retained amino acids residues may be at the N-terminal and/or C-terminal of the (unmodified) BoNT/C (BoNT/C1) activation loop. In some preferred embodiments, the endogenous activation loop is completely replaced in an engineered clostridial neurotoxin of the invention. Typically this means that all the amino acid residues of the activation loop (between the cysteine residues which form the disulphide bond in the active di-chain molecule) are replaced by an exogenous activation loop, modified BoNT/C (BoNT/C1) activation loop or exogenous protease cleavage site according to the invention. Complete replacement of the endogenous activation loop may comprise the introduction of a exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop which consists entirely of one or more exogenous protease cleavage site as described herein. Alternatively, complete replacement of the endogenous activation loop may comprise the introduction of a exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop which comprises one or more exogenous protease cleavage site as described herein, together with one or more spacer sequence. Each one or more spacer sequence is typically a short peptide (e.g. between about 5 to about 25 amino acids, such as between about 5 to about 20 amino acids, between about 5 to about 15 amino acids, or between about 5 to about 10 amino acids). Such spacers may be present when the one or more exogenous protease cleavage site is a short motif (e.g. typically less than 15, preferably less than 10 or less than 9 amino acids in length). One or more spacer may be present N-terminal and/or C-terminal to each of said exogenous protease cleavage sites. Preferably, a spacer may be a GS spacer as defined herein. Replacement (including partial replacement) of an endogenous activation loop or an (unmodified) BoNT/C (BoNT/C1) activation loop with one or more exogenous protease cleavage site may be achieved by any method known in the art. For example, replacement might be achieved by way of an amino acid modification. An endogenous activation loop may be replaced by deleting one or more amino acid residues of the endogenous activation loop. An endogenous activation loop may be replaced by substituting one or more amino acid residues of the endogenous activation loop with amino acid residues of an exogenous activation loop. An endogenous activation loop (or a portion thereof) may be deleted, and one or more exogenous protease cleavage site or an exogenous activation loop comprising one or more exogenous protease cleavage site inserted, preferably at the position formally occupied by the endogenous activation loop. Alternatively, the endogenous activation loop may be retained in an engineered clostridial neurotoxin of the invention, and preferably inactivated (e.g. by way of mutation). It is preferred that the endogenous activation loop (a portion thereof or the entire endogenous activation loop) is not present in the engineered clostridial neurotoxin of the invention. It is preferred that the one or more exogenous protease cleavage site or the exogenous activation loop comprising the one or more exogenous protease cleavage site occupies the position in the clostridial neurotoxin formally occupied by the endogenous activation loop. For the avoidance of doubt, when an endogenous activation loop is modified to comprise one or more exogenous protease cleavage site (e.g. by substitution of residues within the endogenous activation loop or by the addition of one or more amino acids to form one or more exogenous protease cleavage site within the endogenous activation loop), the modified activation loop is an exogenous activation loop according to the invention. Therefore, potentially an engineered clostridial neurotoxin can comprise both its endogenous activation/cleavage site and one or more exogenous protease cleavage site, and as such may be activated either by the native activating protease (or equivalents used in conventional recombinant BoNT production, e.g. trypsin or Lys-C), or by one or more exogenous protease. For example, replacement (including partial replacement) of the unmodified BoNT/C (BoNT/C1) activation loop, and/or replacement (including partial replacement) of the endogenous BoNT/C (BoNT/C) activation site might be achieved by way of an amino acid modification. An unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site may be replaced by deleting one or more amino acid residues of the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site. An unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site may be replaced by substituting one or more amino acid residues of the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site with amino acid residues of an exogenous protease cleavage site. An unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site (or a portion thereof) may be deleted, and one or more exogenous protease cleavage site inserted, preferably at the position formally occupied by the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site. Alternatively, the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site may be retained in an engineered clostridial neurotoxin of the invention, and preferably inactivated (e.g. by way of mutation). It is preferred that the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site (or a portion thereof) is not present in the engineered clostridial neurotoxin of the invention. It is preferred that the one or more exogenous protease cleavage site occupies the position in the clostridial neurotoxin formally occupied by the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site. For the avoidance of doubt, when an unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site is modified to comprise one or more exogenous protease cleavage site (e.g. by substitution of residues within the unmodified BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site or by the addition of one or more amino acids to form one or more exogenous protease cleavage site within the BoNT/C (BoNT/C1) activation loop, and/or endogenous BoNT/C (BoNT/C) activation site), the modified BoNT/C (BoNT/C1) activation loop, and/or modified BoNT/C (BoNT/C) activation site is an exogenous activation loop according to the invention. Therefore, potentially an engineered clostridial neurotoxin can comprise both its endogenous activation/cleavage site and one or more exogenous protease cleavage site, and as such may be activated either by the native activating protease (or equivalents used in conventional recombinant BoNT production, e.g. trypsin or Lys-C), or by one or more exogenous protease. In particular, a BoNT/C (BoNT/C1) activation loop, and/or BoNT/C (BoNT/C) activation site may be modified by (i) substitution of one or more amino acid present within the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site; and/or (ii) insertion of one or more amino acid into the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site. Preferably, a BoNT/C (BoNT/C1) activation loop, and/or BoNT/C (BoNT/C) activation site may be modified by (i) substitution of one or more amino acid present within the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site; or (ii) substitution of one or more amino acid present within the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site and insertion of one or more amino acid into the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site. Between 1-10 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids of the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site may be substituted to form a modified BoNT/C (BoNT/C1) activation loop and/or modified BoNT/C (BoNT/C) activation site, such as between about 3-10, 3-9, 5-9, or 5-8 amino acids may be substituted. Alternatively or additionally, between 1-10 (e.g.1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acids may be inserted into the unmodified BoNT/C (BoNT/C1) activation loop, and/or unmodified/endogenous BoNT/C (BoNT/C) activation site to form a modified BoNT/C (BoNT/C1) activation loop and/or modified BoNT/C (BoNT/C) activation site, such as between about 3-10, 3-9, 4-8, or 4-7 amino acids may be inserted. Methods for modifying proteins by substitution, insertion or deletion of amino acid residues are known in the art and may be employed in the practice of the present invention. By way of example, amino acid modifications may be introduced by modification of a DNA sequence encoding a clostridial neurotoxin. This can be achieved using standard molecular cloning techniques, for example by site-directed mutagenesis where short strands of DNA (oligonucleotides) coding for the desired amino acid(s) are used to replace the original coding sequence using a polymerase enzyme, or by inserting/deleting parts of the gene with various enzymes (e.g., ligases and restriction endonucleases). Alternatively a modified gene sequence can be chemically synthesised. Any other method known in the art for modifying polypeptides, such as polypeptide synthesis and polypeptide conjugation may also be used to engineer a clostridial neurotoxin according to the invention. An endogenous activation loop replaced according to the invention may comprise or consist of a polypeptide sequence having at least 70% (e.g. at least 80% or 90%) sequence identity to SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83 SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89 or SEQ ID NO: 90. An endogenous activation loop replaced according to the invention may comprise or consist of a polypeptide sequence having at least 70% (e.g. at least 80% or 90%) sequence identity to SEQ ID NO: 90. In particular, an endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83 SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89 or SEQ ID NO: 90. An endogenous activation loop replaced according to the invention may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 90. Preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83 SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89 or SEQ ID NO: 90. An endogenous activation loop replaced according to the invention may comprise or consist of a polypeptide sequence of SEQ ID NO: 90. An endogenous activation loop replaced according to the invention may comprise or consist of a polypeptide sequence having at least 70% (e.g. at least 80% or 90%) sequence identity to SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73,SEQ ID NO: 74 or SEQ ID NO: 90. An endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, or SEQ ID NO: 90. Preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74 , or SEQ ID NO: 90. Preferably an endogenous activation loop replaced according to the invention comprises or consists of a polypeptide sequence having at least 70% (e.g. at least 80% or 90%) sequence identity to SEQ ID NO: 72 or SEQ ID NO: 90. An endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 72 or SEQ ID NO: 90. More preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 72 or SEQ ID NO: 90. The present invention encompasses methods and engineered clostridial neurotoxins in which an endogenous activation loop has been replaced by an exogenous cleavage site, which is one or more exogenous protease cleavage site, or an exogenous activation loop which comprises one or more exogenous protease cleavage site, as described herein. The present invention encompasses methods and engineered clostridial neurotoxins in which an endogenous activation loop has been replaced by a modified BoNT/C (BoNT/C1) activation loop, wherein the endogenous activation site of the BoNT/C (BoNT/C1) activation loop (or part thereof) has been replaced by one or more exogenous protease cleavage site as described herein. The engineered clostridial neurotoxins of the invention may comprise an exogenous activation loop comprising one or more of any exogenous protease cleavage site as described herein. An exogenous activation loop may be produced by replacing one or more amino acids of an endogenous activation loop of a clostridial neurotoxin, as described herein. In some preferred embodiments, the replaced amino acids of the endogenous activation loop are replaced by one or more exogenous protease cleavage site or exogenous activation loop having the same number of amino acids. In other words, by way of illustration, if five amino acids are replaced in an endogenous activation loop, the replacement one or more exogenous protease cleavage site or exogenous activation loop comprising said one or more exogenous protease cleavage site has five amino acids. If ten amino acids are replaced in an endogenous activation loop, the replacement one or more exogenous protease cleavage site or exogenous activation loop comprising said one or more exogenous protease cleavage site has ten amino acids. Non-limiting examples of such exogenous activation loops include, SEQ ID NOs: 53- 66. The engineered clostridial neurotoxins of the invention may comprise a modified BoNT/C (BoNT/C1) activation loop comprising one or more of any exogenous protease cleavage site as described herein. A modified BoNT/C (BoNT/C1) activation loop may be produced by replacing one or more amino acids of the unmodified BoNT/C (BoNT/C1) activation loop of a clostridial neurotoxin, as described herein. In some preferred embodiments, the replaced amino acids of the unmodified BoNT/C (BoNT/C1) activation loop are replaced by one or more exogenous protease cleavage site having the same number of amino acids. In other words, by way of illustration, if five amino acids are replaced in an unmodified BoNT/C (BoNT/C1) activation loop, the replacement one or more exogenous protease cleavage site has five amino acids. If ten amino acids are replaced in an unmodified BoNT/C (BoNT/C1) activation loop, the replacement one or more exogenous protease cleavage site has ten amino acids. Non-limiting examples of such modified BoNT/C (BoNT/C1) activation loops are derived herein. The invention provides a method for manufacturing an engineered clostridial neurotoxin according to the invention, comprising replacing an endogenous activation loop (or part thereof) of a clostridial neurotoxin by an exogenous activation loop or an exogenous cleavage site or a modified BoNT/C (BoNT/C1) activation loop, thereby providing an exogenous clostridial neurotoxin, wherein the exogenous cleavage site is one or more exogenous protease cleavage site as described herein, or the exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop comprises said one or more exogenous protease cleavage site. Typically said one or more exogenous protease cleavage site is selected from a sequence which comprises or consists of the amino acid sequence of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred, or the exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop comprises said one or more exogenous protease cleavage site. The invention provides an engineered clostridial neurotoxin (e.g. obtainable by a method of the invention), wherein an endogenous activation loop (or part thereof) of a clostridial neurotoxin has been replaced by an exogenous activation loop, an exogenous cleavage site or a modified BoNT/C (BoNT/C1) activation loop, thereby providing an engineered clostridial neurotoxin, wherein the exogenous cleavage site is one or more exogenous protease cleavage site as described herein, or the exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop comprises said one or more exogenous protease cleavage site. Typically said one or more exogenous protease cleavage site is selected from a sequence which comprises or consists of the amino acid sequence of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred, or the exogenous activation loop comprises said one or more exogenous protease cleavage site. A clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) may be encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 70% sequence identity to any one of SEQ ID NOs: 154, 156, or 158. A clostridial neurotoxin of the present invention may be encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 80% or 90% sequence identity to any one of SEQ ID NOs: 154, 156, or 158. Preferably, a clostridial neurotoxin of the present invention may be encoded by a nucleic acid comprising or consisting of a nucleotide sequence comprising (more preferably consisting of) any one of SEQ ID NOs: 154, 156, or 158. A clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) may comprise or consist of a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 155, 157, 159, 166, 167 or 168. A clostridial neurotoxin of the present invention may comprise or consist of a polypeptide sequence having at least 80% or 90% sequence identity to one or more of SEQ ID NOs: 155, 157, 159, 166, 167 or 168. Preferably, a clostridial neurotoxin of the present invention may comprise or consist of (more preferably consist of) a polypeptide sequence shown as any one of SEQ ID NOs: 155, 157, 159, 166, 167 or 168. The clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) is preferably BoNT/X, wherein the clostridial neurotoxin is encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 160, 162 or 164. The clostridial neurotoxin may be encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 160, 162 or 164. Preferably the clostridial neurotoxin is encoded by a nucleic acid comprising or consisting of a nucleotide sequence comprising (or consisting of) SEQ ID NO: 160, 162 or 164. The clostridial neurotoxin of the present invention is preferably BoNT/X, wherein the clostridial neurotoxin comprises or consists of a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 161, 163, 165, 166, 167 or 168. The clostridial neurotoxin may comprise or consist of a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 161, 163, 165, 166, 167 or 168. Preferably the clostridial neurotoxin comprises (or consists of) a polypeptide sequence shown as SEQ ID NO: 161, 163, 165, 166, 167 or 168. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease cleavage site or a modified BoNT/C activation loop as defined herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease cleavage site or a modified BoNT/C activation loop as defined herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be a single- chain clostridial neurotoxin encoded by a nucleic acid comprising or consisting of the nucleotide sequence of SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease cleavage site or a modified BoNT/C activation loop as defined herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. Alternatively or in addition, the engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin comprising or consisting of a polypeptide sequence having (i) at least 70% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 70% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin comprising or consisting of a polypeptide sequence having (i) at least 80% or 90% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 80% or 90% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin comprising or consisting of (i) the polypeptide sequence of SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) the polypeptide sequence of SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The polypeptide sequences of the invention (or the nucleotide sequences encoding the same) may include a purification tag, such as a His-tag. It is intended that the present invention also encompasses polypeptide sequences (and nucleotide sequences encoding the same) where the purification tag is removed. Exogenous Proteases and Exogenous Protease Cleavage Sites An exogenous protease according to the invention is a protease which (i) is not responsible for cleaving native clostridial holotoxins (i.e. is not a clostridial hydrolase); and (ii) is typically not used in conventional manufacturing of clostridial neurotoxins (e.g. trypsin and/or Lys-C). The term “exogenous” refers to the relationship between the endogenous clostridial activation loop and the protease. As such, a protease which is present with a patient to be treated may be considered an exogenous protease in the context of activating an engineered clostridial neurotoxin of the invention, although said protease could be described as endogenous to the patient to be treated. Accordingly, non-limiting examples of exogenous protease according to the present invention may be selected from thrombin; tissue plasminogen activator (t-PA); urokinase (u- PA); Factor IX (FIX); Factor VIIa (FVIIa) and/or plasminogen. These proteases have a variety of different functions, and are typically involved in the formation or degradation of blood clots in vivo. Preferably the exogenous protease is selected from thrombin, t-PA and/or u-PA, with thrombin being particularly preferred. The exogenous protease is typically a human protease, such as a recombinant human protease. Alternatively or in addition, the exogenous protease may be comprised in a drug product. In other words, engineered clostridial neurotoxins of the invention typically comprises at least one cleavage site for one or more of thrombin, t-PA, u-PA, FIX, FVIIa and/or plasminogen. Preferably an engineered clostridial neurotoxin of the invention comprises at least one cleavage site for one or more of thrombin, t-PA and/or u-PA, with at least one cleavage site for thrombin being particularly preferred. Thrombin is a serine protease which hydrolyses peptide bonds following arginine or lysine residues, including Xaa ₁ -Xaa ₂ -Pro/Ala/Leu/Gly-Arg // Ser/Ala/Gly-Xaa ₃ -Xaa ₄ -Xaa ₅ , (SEQ ID NO: 18) where Xaa _1-5 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “thrombin” encompasses thrombin as described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing a peptide bond of the consensus Xaa ₁ -Xaa ₂ -Pro/Ala/Leu/Gly-Arg // Ser/Ala/Gly- Xaa ₃ -Xaa ₄ -Xaa ₅ . A suitable thrombin is human thrombin, which has UniProt Accession No. P00734 (version 2 of the sequence, deposited 01 January 1990, accessed 04 September 2022), herein SEQ ID NO: 23. This sequence is a propeptide, which is converted to the mature human form by a process involving cleavage of an N-terminal polypeptide of residues 1-271 to form prethrombin 2 (P2), which is then further cleaved at Arg320 to yield thrombin. Human thrombin is commercially available from Merck (#69671). Tissue plasminogen activator (t-PA or tPA) is a serine protease, cleaving in a range of consensus sequences, including (i) cleaving after the arginine residue in the consensus Arg-Val; (ii) Xaa1-Phe/Tyr-Ser/Gly/Ala-Arg // Xaa2-Xaa3-Xaa4-Xaa5, (SEQ ID NO: 34) where Xaa1-5 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond; and/or (iii) Gly-Pro-Xaa1-Lys/Arg // Xaa2-Gly-Gly- Xaa3 (SEQ ID NO: 35), where Xaa1-3 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “t-PA” encompasses t-PA described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing a peptide bond of the consensus Arg-Val, Xaa1-Phe/Tyr-Ser/Gly/Ala-Arg // Xaa1- Xaa2- Xaa3-Xaa4, or Gly-Pro- Xaa1-Lys/Arg // Xaa2-Gly-Gly- Xaa3. A suitable t-PA is human t-PA, which has UniProt Accession No. P00750 (version 1 of the sequence, deposited 21 July 1986, accessed 11 September 2022), herein SEQ ID NO: 43. This sequence is a propeptide, which is converted to the mature human form by a process involving cleavage of an N-terminal polypeptide of residues 1-35. Human t-PA is commercially available from Merck (#T0831). Urokinase (also referred to as urokinase plasminogen activator, u-PA or uPA) is a serine protease, cleaving in a range of consensus sequences , including (i) cleaving after the arginine residue in the consensus Arg-Val; and/or (ii) Xaa ₁ -Ser-Gly/Ser-Arg/Lys // Gly- Leu/Arg/Val-Xaa ₂ -Asn/Gly (SEQ ID NO: 28), where Xaa _1-2 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “u-PA” encompasses u-PA described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing a peptide bond of the consensus Arg-Val or Xaa ₁ -Ser-Gly/Ser-Arg/Lys // Gly-Leu/Arg/Val-Xaa ₂ -Asn/Gly. A suitable u-PA is human u-PA, which has UniProt Accession No. P29598 (version 1 of the sequence, deposited 01 April 1993, accessed 11 September 2022), herein SEQ ID NO: 31. This sequence is a propeptide, which is converted to the mature human form by a process involving cleavage of an N-terminal polypeptide of residues 1-158. Human u-PA is commercially available from Merck (#672112). Factor IX (FIX) is a serine protease cleaving in a range of consensus sequences, including (i) cleaving after the arginine residue in the consensus Arg-Ile; and/or (ii) Xaa ₁ - Xaa ₂ - Gly-Arg // Xaa ₃ -Xaa ₄ -Xaa ₅ -Xaa ₆ (SEQ ID NO: 45), where Xaa _1-6 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “Factor IX” encompasses FIX described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing a peptide bond of the consensus Arg-Ile or Xaa1- Xaa2-Gly-Arg // Xaa3-Xaa4-Xaa5-Xaa6. A suitable FIX is human FIX, which has UniProt Accession No. P00740 (version 2 of the sequence, deposited 07 June 2005, accessed 11 September 2022), herein SEQ ID NO: 47. This sequence is a propeptide, which is converted to the mature human form by a process involving cleavage of an N-terminal polypeptide of residues 1-46. Human FIX is commercially available from Merck (#233279). Factor VIIa (FVIIa) is a serine protease cleaving in a range of consensus sequences, including cleaving after the arginine residue in the motif Arg-Ile. The term “factor VIIa” encompasses FVIIa described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing a peptide bond of the consensus Arg-Ile. A suitable FVIIa is human FVIIa, which has UniProt Accession No. P08709 (version 1 of the sequence, deposited 01 January 1988, accessed 11 September 2022), herein SEQ ID NO: 48. This sequence is a propeptide, which is converted to the mature human form by a process involving cleavage of an N-terminal polypeptide of residues 1-60. Human FVIIa is commercially available from Merck (# P08709). Plasminogen is a serine protease cleaving in a range of consensus sequences, including (i) cleaving after the lysine residue in the consensus Lys-Xaa, where Xaa is any amino acid; and/or (ii) after the arginine residue in the consensus Arg-Xaa, where Xaa is any amino acid. The term “plasminogen” encompasses plasminogen described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing a peptide bond of the consensus Lys-Xaa or Arg-Xaa. A suitable plasminogen is human plasminogen, which has UniProt Accession No. P00747 (version 1 of the sequence, deposited 01 July 1989, accessed 11 September 2022), herein SEQ ID NO: 49. This sequence is a propeptide, which is converted to the mature human form (plasmin) by a process involving cleavage of a peptide bond between Arg580 and Val581. Human AEP is commercially available from Merck (# 528185). For in vitro and ex vivo uses, it is within the routine practice of one of ordinary skill in the art to determine the appropriate concentration/unit amount of any exogenous protease to activate an engineered clostridial neurotoxin of the invention under standard/desired conditions. In the context of the invention the term “thrombin” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 23, or the mature form thereof. Thus, “thrombin” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 23, or the mature form thereof. Preferably a thrombin comprises (more preferably consists of) SEQ ID NO: 23, or the mature form thereof. In the context of the invention the term “tissue plasminogen activator” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 43, or the mature form thereof. Thus, “t-PA” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 43, or the mature form thereof. Preferably a t-PA comprises (more preferably consists of) SEQ ID NO: 43, or the mature form thereof. In the context of the invention the term “urokinase” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 31, or the mature form thereof. Thus, “u-PA” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 31, or the mature form thereof. Preferably a u-PA comprises (more preferably consists of) SEQ ID NO: 31, or the mature form thereof. In the context of the invention the term “Factor IX” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 47, or the mature form thereof. Thus, “FIX” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 47, or the mature form thereof. Preferably a FIX comprises (more preferably consists of) SEQ ID NO: 47, or the mature form thereof. In the context of the invention the term “Factor VIIa” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 48, or the mature form thereof. Thus, “FVIIa” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 48, or the mature form thereof. Preferably a FVIIa comprises (more preferably consists of) SEQ ID NO: 48, or the mature form thereof. In the context of the invention the term “plasminogen” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 49. Thus, “plasminogen” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 49, or the mature form thereof. Preferably a plasminogen comprises (more preferably consists of) SEQ ID NO: 49. When describing exogenous protease cleavage sites of the invention, It is not intended that any Xaa (e.g. Xaa ₁ , Xaa ₂ , Xaa ₃ , Xaa ₄ , Xaa ₅ or Xaa ₆ ) be limited to only one type of amino acid. Thus, one or more residues present at any Xaa may be independently selected from the standard amino acids: aspartic acid, glutamic acid, arginine, lysine, histidine, asparagine, glutamine, serine, threonine, tyrosine, methionine, tryptophan, cysteine, alanine, glycine, valine, leucine, isoleucine, proline, and phenylalanine. Alternatively/additionally, one or more residues present at any Xaa (e.g. Xaa ₁ , Xaa ₂ , Xaa ₃ , Xaa ₄ , Xaa ₅ or Xaa ₆ ) may be independently selected from a non-standard amino acid (an amino acid that is not part of the standard set of 20 described above). By way of example, non-standard amino acids may include 4-hydroxyproline, 6-N-methyl lysine, 2-aminoisobutyric acid, isovaline, α -methyl serine, trans-3-methylproline, 2,4-methano-proline, cis-4- hydroxyproline, trans-4-hydroxy-proline, N-methylglycine, allo-threonine, methyl-threonine, hydroxy-ethylcysteine, hydroxyethylhomo-cysteine, nitro-glutamine, homoglutamine, pipecolic acid, tert-leucine, norvaline, 2-azaphenylalanine, 3-azaphenyl-alanine, 4-azaphenyl-alanine, L-Ornithine, L-2-amino-3-guanidinopropionic acid, or D-isomers of Lysine, Arginine and/or Ornithine, and 4-fluorophenylalanine. Methods for introducing non-standard amino acids into proteins are known in the art, and include recombinant protein synthesis using E. coli auxotrophic expression hosts. Properties of the standard amino acids are indicated in the table below: The following amino acids are considered charged amino acids: aspartic acid (negative), glutamic acid (negative), arginine (positive), and lysine (positive). Exemplary (typically consensus) cleavage sites for thrombin, t-PA, u-PA, FIX, FVIIa and plasminogen are described herein. An engineered clostridial neurotoxin of the invention may comprise one or more of these cleavage sites. A thrombin cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ X X PALG RK // SAG X X X (SEQ ID NO: 19) and/or X X X RK // X X X X (SEQ ID NO: 20) preferably X X P R // SAG X X X (SEQ ID NO: 21) and/or X X P K // SAG X X X (SEQ ID NO: 22) most preferably AL X PLAG RK // SAG AVL GL X (SEQ ID NO: 169) and/or AL X P R // G AVL GL X (SEQ ID NO: 170) The amino acid residues shown at each position (P4, P3, P2, P1, P1’, P2’, P3’ and P4’) are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “//” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, a thrombin cleavage site may comprise or consist of a consensus sequence selected from XX(PALG)(RK)|(SAG)XXX (SEQ ID NO: 19) and/or XXX(RK)|XXXX (SEQ ID NO: 20), preferably XXPR|(SAG)XXX (SEQ ID NO: 21) and/or XXPK|(SAG)XXX (SEQ ID NO: 22), more preferably (AL)X(PLAG)(RK)|(SAG)(AVL)(GL)X (SEQ ID NO: 169) and/or (AL)XPR|G(AVL)(GL)X (SEQ ID NO: 170); wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, a preferred thrombin cleavage site may comprise or consist of a PRG motif (SEQ ID NO: 171). A t-PA cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ X X X R // V X X X (SEQ ID NO: 29) and/or X FY SGA R // X X X X (SEQ ID NO: 34) and/or S FY SGA R // X X X X (SEQ ID NO: 38) and/or G P X KR // X G G X (SEQ ID NO: 35) and/or G P Y KR // X G G X (SEQ ID NO: 40) and/or G P X KR // K G G X (SEQ ID NO: 41) and/or G P Y KR // K G G X (SEQ ID NO: 42) The amino acid residues shown at each position (P4, P3, P2, P1, P1’, P2’, P3’ and P4’) are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “//” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, a t-PA cleavage site may comprise or consist of a consensus sequence selected from XXXR|VXXX (SEQ ID NO: 29), and/or X(FY)(SGA)R|XXXX (SEQ ID NO: 34), and/or S(FY)(SGA)R|XXXX (SEQ ID NO: 38), and/or GPX(KR)|XGGX (SEQ ID NO: 35), and/or GPY(KR)|XGGX (SEQ ID NO: 40), and/or GPX(KR)|KGGX (SEQ ID NO: 41), and/or GPY(KR)|KGGX (SEQ ID NO: 42); wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). A u-PA cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ X X X R // V X X X (SEQ ID NO: 29) and/or X S GS RK // G LRV X NG (SEQ ID NO: 28) preferably X X X R // V X X X (SEQ ID NO: 29) and/or X S G R // G LRV X NG (SEQ ID NO: 30) The amino acid residues shown at each position (P4, P3, P2, P1, P1’, P2’, P3’ and P4’) are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “//” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, a u-PA cleavage site may comprise or consist of a consensus sequence selected from XXXR|VXXX (SEQ ID NO: 29), and/or XS(GS)(RK)|G(LRV)X(NG) (SEQ ID NO: 28), preferably XXXR|VXXX (SEQ ID NO: 29), and/or XSGR|G(LRV)X(NG) (SEQ ID NO: 30); wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). A u-PA and/or t-PA cleavage site may preferably comprise or consist of a consensus sequence selected from: P5 P4 P3 P2 P1 // P1’ P2’ P GPAL SGF GS RK // SGV AVLR (SEQ ID NO: 172) and/or P5 P4 P3 P2 P1 // P1’ P2’ P GPAL SGF G R // S A (SEQ ID NO: 173) Thus, a preferred u-PA and/or t-PA cleavage site may comprise or consist of a consensus sequence selected from P(GPAL)(SGF)(GS)(RK)|(SGV)(AVLR) (SEQ ID NO: 172), and/or P(GPAL)(SGF)GR|SA (SEQ ID NO: 173), wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, a preferred u-PA and/or t-PA cleavage site may comprise or consist of a GRSA motif (SEQ ID NO: 174). An FIX cleavage site may comprise or consist of a consensus sequence of: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ X X X R // I X X X (SEQ ID NO: 46) and/or X X G R // X X X X (SEQ ID NO: 45) The amino acid residues shown at each position (P4, P3, P2, P1, P1’, P2’, P3’ and P4’) are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “//” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, an FIX cleavage site may comprise or consist of a consensus sequence of XXXR|IXXX (SEQ ID NO: 46), and/or XXGR|XXXX (SEQ ID NO: 45); wherein each X may be independently selected from any amino acid, and the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). An FVIIa cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ X X X R // I X X X (SEQ ID NO: 46) The amino acid residues shown at each position (P4, P3, P2, P1, P1’, P2’, P3’ and P4’) are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “//” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, an FVIIa cleavage site may comprise or consist of a consensus sequence selected from XXXR|IXXX (SEQ ID NO: 46); wherein each X may be independently selected from any amino acid, and the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). A plasminogen cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ X X X K // X X X X (SEQ ID NO: 51) and/or X X X R // X X X X (SEQ ID NO: 52) The amino acid residues shown at each position (P4, P3, P2, P1, P1’, P2’, P3’ and P4’) are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “//” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). Thus, a plasminogen cleavage site may comprise or consist of a consensus sequence selected from XXXR|XXXX (SEQ ID NO: 52), and/or XXXK|XXXX (SEQ ID NO: 51); wherein each X may be independently selected from any amino acid, and the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). An exogenous protease cleavage site of the invention may be formed by the insertion of a peptide that is less than 10 amino acids in length, such as between about 3 to 9 about 9 amino acids in length, or between about 3 to about 8 amino acids in length. Thus, an exogenous protease cleavage site of the invention may be formed by the insertion of a peptide that is typically 3, 4, 5, 6, 7, 8 or 9 amino acids in length. An exogenous protease cleavage site of the invention may comprise or consist of one or more of: LTPRGVRL (SEQ ID NO: 15), LVPRGS (SEQ ID NO: 16), ENKSLVPRGS (SEQ ID NO: 17), KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), VVPRVELVA (SEQ ID NO: 32), PPFGRSAG (SEQ ID NO: 33), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27), GRI (SEQ ID NO: 44) or PGRVVGG (SEQ ID NO: 50). An exogenous protease cleavage site of the invention may be a thrombin cleavage site, i.e. the exogenous protease cleavage site may be specific for thrombin. Such a thrombin cleavage site may comprise or consist of LTPRGVRL (SEQ ID NO: 15), ENKSLVPRGS (SEQ ID NO: 17) or LVPRGS (SEQ ID NO: 16), preferably LTPRGVRL (SEQ ID NO: 15) or ENKSLVPRGS (SEQ ID NO: 17). A thrombin cleavage site of LTPRGVRL (SEQ ID NO: 15) is particularly preferred. An exogenous protease cleavage site of the invention may be a t-PA and/or u-PA cleavage site, i.e. the exogenous protease cleavage site may be specific for t-PA and/or u- PA. Such a t-PA and/or u-PA cleavage site may comprise or consist of KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), VVPRVELVA (SEQ ID NO: 32) or PPFGRSAG (SEQ ID NO: 33), preferably SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26) or PGSGRSASGTTGTG (SEQ ID NO: 27) or PPFGRSAG (SEQ ID NO: 33). A t-PA and/or u-PA cleavage site of PPFGRSAG (SEQ ID NO: 33) and/or PGSGRSAG (SEQ ID NO: 26) may be particularly preferred. An exogenous protease cleavage site of the invention may be a u-PA cleavage site, i.e. the exogenous protease cleavage site may be specific for u-PA. Such a u-PA cleavage site may comprise or consist of KRV (SEQ ID NO: 24), SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26), PGSGRSASGTTGTG (SEQ ID NO: 27) or PPFGRSAG (SEQ ID NO: 33), preferably SGRSA (SEQ ID NO: 25), PGSGRSAG (SEQ ID NO: 26) or PGSGRSASGTTGTG (SEQ ID NO: 27). A u-PA cleavage site of PGSGRSAG (SEQ ID NO: 26) may be particularly preferred. An exogenous protease cleavage site of the invention may be a t-PA cleavage site, i.e. the exogenous protease cleavage site may be specific for t-PA. Such a t-PA cleavage site may comprise or consist of SGRSA (SEQ ID NO: 25), VVPRVELVA (SEQ ID NO: 32) or PPFGRSAG (SEQ ID NO: 33), preferably PPFGRSAG (SEQ ID NO: 33) or SGRSA (SEQ ID NO: 25). A t-PA cleavage site of PPFGRSAG (SEQ ID NO: 33) may be particularly preferred. An exogenous protease cleavage site of the invention may be an FIX and/or FVIIa cleavage site, i.e. the exogenous protease cleavage site may be specific for FIX and/or FVIIa. Such a FIX and/or FVIIa cleavage site may comprise or consist of GRI (SEQ ID NO: 44). An exogenous protease cleavage site of the invention may be a plasminogen cleavage site, i.e. the exogenous protease cleavage site may be specific for plasminogen. Such a plasminogen cleavage site may comprise or consist of PGRVVGG (SEQ ID NO: 50). An engineered clostridial neurotoxin of the invention may comprise one or more exogenous protease cleavage site as defined herein. In some embodiments an exogenous protease cleavage site of the invention has at least 70% sequence identity to any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred. An exogenous protease cleavage site may have at least 80%, 85% or 90% sequence identity to any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred. [. Preferably an exogenous protease cleavage site has at least 95% sequence identity to any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred. More preferably, an exogenous protease cleavage site has at least 99% sequence identity to any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15- 22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred. Particularly preferred is an exogenous protease cleavage site comprising or consisting of any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50-52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32- 42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred. Typically said exogenous protease cleavage site comprises or consists of one or more of the amino acid sequence of any one of SEQ ID NOs: 15-22, 24-30, 32-42, 44-46 and/or 50- 52, particularly SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred, or the exogenous activation loop comprises said one or more exogenous protease cleavage site. An engineered clostridial neurotoxin of the invention may comprise one or more exogenous protease cleavage site. In other words, an engineered clostridial neurotoxin of the invention may comprise one exogenous protease cleavage site as described herein, or multiple exogenous protease cleavage sites. An engineered clostridial neurotoxin of the invention may comprise two, three, four, five, six, seven, eight, nine, ten or more exogenous protease cleavage sites. By way of non-limiting example, an engineered clostridial neurotoxin of the invention may comprise 2 to 7 (2, 3, 4, 5, 6 or 7) exogenous protease cleavage site. When an engineered clostridial neurotoxin of the invention comprises multiple exogenous protease cleavage sites, these may each be selected independently. Typically, when an engineered clostridial neurotoxin of the invention comprises multiple exogenous protease cleavage sites, each exogenous protease cleavage site may independently be selected from the exogenous protease cleavage sites described herein. Thus, an engineered clostridial neurotoxin of the invention may comprise multiple exogenous protease cleavage sites that are each different from each other, or an engineered clostridial neurotoxin of the invention may comprise two or more copies of a specific exogenous protease cleavage sites, or any combination thereof. Multiple exogenous protease cleavage sites may be introduced at a single location within a clostridial neurotoxin. Alternatively, multiple exogenous protease cleavage sites may be introduced at multiple locations within a clostridial neurotoxin. By way of non-limiting example, one exogenous protease cleavage site may be introduced within the activation loop or modified BoNT/C (BoNT/C1) activation loop within a clostridial neurotoxin and another (same or different) exogenous protease cleavage site may be introduced within the LHN domain. Typically, where multiple exogenous protease cleavage sites are introduced into an engineered clostridial neurotoxin according to the invention, they are introduced at a single location within a clostridial neurotoxin. Preferably, where multiple exogenous protease cleavage sites are introduced into an engineered clostridial neurotoxin according to the invention, they are each introduced within the activation loop or modified BoNT/C (BoNT/C1) activation loop of the clostridial neurotoxin. The relative positioning of individual exogenous protease cleavage sites within an exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop of the invention may be determined by the structure-function relationship for the exogenous protease in question. It is within the routine practice of one of ordinary skill in the art to appropriately position individual exogenous protease cleavage sites within an exogenous activation loop or modified BoNT/C (BoNT/C1) activation loop comprising multiple exogenous protease cleavage site based on this structure-function relationship, without undue burden. The exogenous protease cleavage site may be comprises within a modified clostridial toxin activation loop. Said modified clostridial toxin activation loop may be from the same serotype as the engineered clostridial neurotoxin, or a different serotype to the engineered clostridial neurotoxin. Typically said modified clostridial toxin activation loop is from a different serotype as the engineered clostridial neurotoxin. Preferably, said modified clostridial activation loop is from BoNT/C or BoNT/A, with a modified clostridial activation loop from BoNT/C being particularly preferred. A modified clostridial activation loop is one in which the endogenous activation site, or part thereof, has been replaced by an exogenous protease cleavage site as described herein. Preferably, a modified clostridial activation loop may be (i) a BoNT/C activation loop in which the endogenous BoNT/C activation site, or part thereof, has been replaced by an exogenous protease cleavage site as defined herein; or (ii) a BoNT/A activation loop in which the endogenous BoNT/A activation site, or part thereof, has been replaced by an exogenous protease cleavage site as defined herein. A modified clostridial activation loop which is a BoNT/C activation loop in which the endogenous BoNT/C activation site, or part thereof, has been replaced by an exogenous protease cleavage site as defined herein, is particularly preferred. As described herein, one or more exogenous protease cleavage site may be comprised in an exogenous activation loop or modified BoNT/C activation loop together with one or more spacer sequence as defined herein. Spacer sequences may typically be present when the one or more exogenous protease cleavage site is a short motif (e.g. typically less than 15, preferably less than 10 or less than 9 amino acids in length). One or more spacer may be present N-terminal and/or C-terminal to each of said exogenous protease cleavage sites. Preferably, a spacer may be a GS spacer as defined herein. An exogenous activation loop or modified BoNT/C activation loop may comprise one or more exogenous protease cleavage site (e.g. two, three, four or five exogenous protease cleavage sites, typically two or three exogenous protease cleavage sites). Said one or more exogenous protease cleavage sites may be cleavable by different exogenous proteases, By way of non-limiting example, an exogenous activation loop or modified BoNT/C activation loop may comprise a thrombin cleavage site and a t-PA cleavage site. Inclusion of one or more exogenous protease cleavage sites within an exogenous activation loop, or modified BoNT/C activation loop wherein said one or more exogenous protease sites are cleavable by different exogenous proteases may increase processing of an engineered clostridial neurotoxin comprising said exogenous activation loop or modified BoNT/C activation loop, particularly in vivo processing of said engineered clostridial neurotoxin. Alternatively, multiple copies of the same exogenous protease cleavage site may be comprised within an exogenous activation loop or modified BoNT/C activation loop. Whether an exogenous activation loop or modified BoNT/C activation loop comprises multiple different exogenous protease cleavage sites or multiple copies of the same exogenous protease cleavage site, said cleavage sites may be directly linked, or may be separated by one or more spacer as described herein. Non-limiting examples of exogenous activation loops, including modified BoNT/C activation loops according to the invention include: wherein substituted residues are shown in bold; inserted residues are shown in italics; plasminogen residues are double-underlined; and the remaining residues are present in the corresponding unmodified clostridial activation loop. An exogenous activation loop or modified BoNT/C activation loop comprising one or more exogenous protease cleavage site may be any length, provided that the architecture of the exogenous activation loop or modified BoNT/C activation loop, and typically the clostridial neurotoxin, is preserved and cleavage at the one or more exogenous protease cleavage site results in the formation of an active di-chain form of the engineered clostridial neurotoxin. The exogenous activation loop or modified BoNT/C activation loop may be between about 10 to about 80, such as between about 10 to about 50, between about 10 to about 40, or between about 10 to about 30 (e.g.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50) amino acids in length, such as between about 15 to about 35 (e.g.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35) amino acids in length, preferably between about 15 to about 30 (e.g.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30) amino acids in length. Particularly preferred are exogenous activation loops or modified BoNT/C activation loops which are 17 amino acids in length, as such exogenous activation loops or modified BoNT/C activation loops are the same length as the endogenous BoNT/C (BoNT/C1) activation loop. Clostridial Neurotoxins The term "neurotoxin" as used herein means any polypeptide that enters a neuron and inhibits neurotransmitter release. This process encompasses the binding of the neurotoxin to a low or high affinity receptor, the internalisation of the neurotoxin, the translocation of the endopeptidase portion of the neurotoxin into the cytoplasm and the enzymatic modification of the neurotoxin substrate. More specifically, the term "neurotoxin" encompasses any polypeptide produced by Clostridium bacteria (clostridial neurotoxins) that enters a neuron and inhibits neurotransmitter release, and such polypeptides produced by recombinant technologies or chemical techniques. It is this di-chain form that is the active form of the toxin. The two chains are termed the heavy chain (H-chain), which has a molecular mass of approximately 100 kDa, and the light chain (L-chain), which has a molecular mass of approximately 50 kDa. A clostridial neurotoxin of the invention may be catalytically active also referred to as active) or catalytically inactive. Preferably a clostridial neurotoxin of the invention is catalytically active. The terms “catalytically active” or “active” as used interchangeably herein refer to a clostridial neurotoxin L-chain (or a clostridial neurotoxin comprising such an L-chain) having non-cytotoxic protease activity. Specifically, active clostridial neurotoxin L-chain has endopeptidase activity and is capable of cleaving a protein of the exocytic fusion apparatus in a target cell. A protein of the exocytic fusion apparatus is preferably a SNARE protein, such as SNAP25, synaptobrevin/VAMP, or syntaxin. The term “catalytically inactive” as used herein in respect of a clostridial neurotoxin L- chain means that said L-chain exhibits substantially no non-cytotoxic protease activity, preferably the term “catalytically inactive” as used herein in respect of a clostridial neurotoxin L-chain means that said L-chain exhibits no non-cytotoxic protease activity. In one embodiment, a catalytically inactive clostridial neurotoxin L-chain is one that does not cleave a protein of the exocytic fusion apparatus in a target cell. The term “substantially no non- cytotoxic protease activity” means that the clostridial neurotoxin L-chain has less than 5% of the non-cytotoxic protease activity of a catalytically active clostridial neurotoxin L-chain, for example less than 2%, 1% or preferably less than 0.1% of the non-cytotoxic protease activity of a catalytically active clostridial neurotoxin L-chain. Non-cytotoxic protease activity can be determined in vitro by incubating a test clostridial neurotoxin L-chain with a SNARE protein and comparing the amount of SNARE protein cleaved by the test clostridial neurotoxin L-chain when compared to the amount of SNARE protein cleaved by a catalytically active clostridial neurotoxin L-chain under the same conditions. Routine techniques, such as SDS-PAGE and Western blotting can be used to quantify the amount of SNARE protein cleaved. Suitable in vitro assays are described in WO 2019/145577 A1, which is incorporated herein by reference. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/A. Exemplary reference BoNT/A sequences are shown as SEQ ID NOs: 91-98 and 135, particularly SEQ ID NOs: 91 and 135. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/B. Exemplary reference BoNT/B sequences are shown as SEQ ID NOs: 99-106, particularly SEQ ID NO: 99. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/C. An exemplary reference BoNT/C1 sequence is shown as SEQ ID NO: 107. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/D. An exemplary reference BoNT/D sequence is shown as SEQ ID NOs: 108. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/E. Exemplary reference BoNT/E sequences are shown as SEQ ID NO: 111- 123, particularly SEQ ID NO: 111. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/F. Exemplary reference BoNT/F sequences are shown as SEQ ID NO: 124- 130, particularly SEQ ID NO: 124. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/G. An exemplary reference BoNT/G sequence is shown as SEQ ID NO: 131. The clostridial neurotoxin (e.g. pre-engineering) may be BoNT/X. An exemplary reference BoNT/X sequence is shown as SEQ ID NO: 133. The clostridial neurotoxin (e.g. pre-engineering) may be TeNT. An exemplary reference TeNT sequence is shown as SEQ ID NO: 134. In some preferred embodiments, clostridial neurotoxin (e.g. pre-engineering) is a BoNT/A, BoNT/B or BoNT/X, or a chimera thereof (e.g. BoNT/AB) as described herein. As discussed above, activated clostridial neurotoxins are formed from two polypeptide chains, the heavy chain (H-chain), which has a molecular mass of approximately 100 kDa, and the light chain (L-chain), which has a molecular mass of approximately 50 kDa. The H- chain comprises a C-terminal targeting component (receptor binding domain or H _C domain) and an N-terminal translocation component (H _N domain). Examples of light chain reference sequences include: Botulinum type A neurotoxin: amino acid residues 1-448 Botulinum type B neurotoxin: amino acid residues 1-440 Botulinum type C1 neurotoxin: amino acid residues 1-441 Botulinum type D neurotoxin: amino acid residues 1-445 Botulinum type E neurotoxin: amino acid residues 1-422 Botulinum type F neurotoxin: amino acid residues 1-439 Botulinum type G neurotoxin: amino acid residues 1-441 Tetanus neurotoxin: amino acid residues 1-457 For recently-identified BoNT/X, the L-chain has been reported as corresponding to amino acids 1-439 thereof, with the L-chain boundary potentially varying by approximately 25 amino acids (e.g. 1-414 or 1-464). Preferably the L-chain in an engineered clostridial neurotoxin of the invention is a BoNT/X L-chain. The above-identified reference sequences should be considered a guide, as slight variations may occur according to sub-serotypes. By way of example, US 2007/0166332 (hereby incorporated by reference in its entirety) cites slightly different clostridial sequences: Botulinum type A neurotoxin: amino acid residues M1-K448 Botulinum type B neurotoxin: amino acid residues M1-K441 Botulinum type C1 neurotoxin: amino acid residues M1-K449 Botulinum type D neurotoxin: amino acid residues M1-R445 Botulinum type E neurotoxin: amino acid residues M1-R422 Botulinum type F neurotoxin: amino acid residues M1-K439 Botulinum type G neurotoxin: amino acid residues M1-K446 Tetanus neurotoxin: amino acid residues M1-A457 Alternatively, clostridial neurotoxin L-chains may be defined as the first amino acid (including or excluding an initial methionine residue) through to the first cysteine residue of the endogenous activation loop. In addition or alternatively, a clostridial neurotoxin L-chain may be defined as the amino acid sequence N-terminal to the cleavage site within the endogenous activation loop. Clostridial neurotoxin L-chains may be defined as a clostridial neurotoxin domain which comprises the metal coordinating HExxH motif (SEQ ID NO: 143), which typically functions to cleave a SNARE protein substrate. The term “light-chain” (or “L-chain”) encompasses variants and fragments thereof, provided said variants and fragments still demonstrate non-cytotoxic protease activity (which can be determined using standard assays known in the art, examples of which are described herein). By way of example, a variant may have at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably at least 95% or at least 98% amino acid sequence homology with a reference L-chain. The term fragment, when used in relation to a L-chain, means a peptide having at least 200, preferably at least 250, more preferably at least 300, even more preferably at least 350, and most preferably at least 400 amino acid residues of the reference L-chain. In the case of a clostridial L-chain, the fragment preferably at least 300, more preferably at least 350, and most preferably at least 400 amino acid residues of the reference L-chain. L-chain ‘fragments’ of the present invention embrace fragments of variant L-chains based on the reference sequences. A clostridial neurotoxin H-chains may be defined as the second cysteine of the endogenous activation loop through to the final amino acid. In addition or alternatively, a clostridial neurotoxin H-chain may be defined as starting from the amino acid sequence C- terminal to the cleavage site within the endogenous activation loop. In addition or alternatively, a clostridial neurotoxin H-chain may be defined as starting from the amino acid C-terminal to the cysteine residue (typically the second cysteine residue) that forms a disulphide bond between the L- and H-chain and so defines the C-terminal of the endogenous activation loop. A Translocation Domain is a molecule that enables translocation of a protease into a target cell such that a functional expression of protease activity occurs within the cytosol of the target cell. Whether any molecule (e.g. a protein or peptide) possesses the requisite translocation function of the present invention may be confirmed by any one of a number of conventional assays. For example, Shone C. (1987) describes an in vitro assay employing liposomes, which are challenged with a test molecule. Presence of the requisite translocation function is confirmed by release from the liposomes of K ⁺ and/ or labelled NAD, which may be readily monitored (see Shone C. (1987) Eur. J. Biochem; vol.167(1): pp.175-180). A further example is provided by Blaustein R. (1987), which describes a simple in vitro assay employing planar phospholipid bilayer membranes. The membranes are challenged with a test molecule and the requisite translocation function is confirmed by an increase in conductance across said membranes (see Blaustein (1987) FEBS Letts; vol.226, no.1: pp. 115-120). Additional methodology to enable assessment of membrane fusion and thus identification of Translocation Domains suitable for use in the present invention are provided by Methods in Enzymology Vol 220 and 221, Membrane Fusion Techniques, Parts A and B, Academic Press 1993. The present invention also embraces variants and/or fragments of translocation domains, so long as the variant domains still demonstrate the requisite translocation activity. By way of example, a variant may have at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably at least 95% or at least 98% amino acid sequence homology with a reference translocation domain. The term fragment, when used in relation to a translocation domain, means a peptide having at least 20, preferably at least 40, more preferably at least 80, and most preferably at least 100 amino acid residues of the reference translocation domain. In the case of a clostridial translocation domain, the fragment preferably has at least 100, preferably at least 150, more preferably at least 200, and most preferably at least 250 amino acid residues of the reference translocation domain (e.g. HN domain). Translocation ‘fragments’ of the present invention embrace fragments of variant translocation domains based on the reference sequences. The Translocation Domain is preferably capable of formation of ion-permeable pores in lipid membranes under conditions of low pH. Preferably it has been found to use only those portions of the protein molecule capable of pore-formation within the endosomal membrane. The Translocation Domain may be obtained from a microbial protein source, in particular from a bacterial or viral protein source. Hence, the Translocation Domain may be a translocating domain of an enzyme, such as a bacterial toxin or viral protein. It is well documented that certain domains of bacterial toxin molecules are capable of forming such pores. It is also known that certain translocation domains of virally expressed membrane fusion proteins are capable of forming such pores. Such domains may be employed in the present invention. The Translocation Domain may be of a clostridial origin, such as the HN domain (or a functional component thereof). HN means a portion or fragment of the H-chain of a clostridial neurotoxin approximately equivalent to the amino-terminal half of the H-chain, or the domain corresponding to that fragment in the intact H-chain. The H _C function of the H-chain may be removed by deletion of the H _C amino acid sequence (either at the DNA synthesis level, or at the post-synthesis level by nuclease or protease treatment). Alternatively, the H _C function may be inactivated by chemical or biological treatment. Thus, the H-chain may be incapable of binding to the Binding Site on a target cell to which native clostridial neurotoxin (i.e. holotoxin) binds. Examples of suitable (reference) Translocation Domains include: Botulinum type A neurotoxin - amino acid residues (449-871) Botulinum type B neurotoxin - amino acid residues (441-858) Botulinum type C neurotoxin - amino acid residues (442-866) Botulinum type D neurotoxin - amino acid residues (446-862) Botulinum type E neurotoxin - amino acid residues (423-845) Botulinum type F neurotoxin - amino acid residues (440-864) Botulinum type G neurotoxin - amino acid residues (442-863) Botulinum type X neurotoxin - amino acid residues (461-890) Tetanus neurotoxin - amino acid residues (458-879) For recently-identified BoNT/X, the translocation domain has been reported as corresponding to amino acids 460-890 thereof, with the L-chain and HC boundaries potentially varying by approximately 10 amino acids (e.g. 461-889 or 454-891). Preferably, the translocation domain of an engineered clostridial neurotoxin of the invention is a BoNT/X translocation domain. The above-identified reference sequence should be considered a guide as slight variations may occur according to sub-serotypes. By way of example, US 2007/0166332 (hereby incorporated by reference thereto) cites slightly different clostridial sequences: Botulinum type A neurotoxin - amino acid residues (A449-K871) Botulinum type B neurotoxin - amino acid residues (A442-S858) Botulinum type C neurotoxin - amino acid residues (T450-N866) Botulinum type D neurotoxin - amino acid residues (D446-N862) Botulinum type E neurotoxin - amino acid residues (K423-K845) Botulinum type F neurotoxin - amino acid residues (A440-K864) Botulinum type G neurotoxin - amino acid residues (S447-S863) Tetanus neurotoxin - amino acid residues (S458-V879) In the context of the present invention, a variety of clostridial neurotoxin H _N regions comprising a translocation domain can be useful in aspects of the present invention with the proviso that these active fragments can facilitate the release of a non-cytotoxic protease (e.g. a clostridial L-chain) from intracellular vesicles into the cytoplasm of the target cell and thus participate in executing the overall cellular mechanism whereby a clostridial neurotoxin proteolytically cleaves a substrate. The H _N regions from the heavy chains of clostridial neurotoxins are approximately 410-430 amino acids in length and comprise a translocation domain. Research has shown that the entire length of a H _N region from a clostridial neurotoxin heavy chain is not necessary for the translocating activity of the translocation domain. Thus, in the context of the present invention a translocation domain can include clostridial neurotoxin H _N regions comprising a translocation domain having a length of, for example, at least 350 amino acids, at least 375 amino acids, at least 400 amino acids and at least 425 amino acids. Also encompassed are clostridial neurotoxin H _N regions comprising translocation domain having a length of, for example, at most 350 amino acids, at most 375 amino acids, at most 400 amino acids and at most 425 amino acids. For further details on the genetic basis of toxin production in Clostridium botulinum and C. tetani, we refer to Henderson et al (1997) in The Clostridia: Molecular Biology and Pathogenesis, Academic press. The term HN embraces naturally-occurring neurotoxin HN portions, and modified HN portions having amino acid sequences that do not occur in nature and/ or synthetic amino acid residues, so long as the modified HN portions still demonstrate the above-mentioned translocation function. Alternatively, the Translocation Domain may be of a non-clostridial origin. Examples of non-clostridial (reference) Translocation Domain origins include, but not be restricted to, the translocation domain of diphtheria toxin (O’Keefe et al., Proc. Natl. Acad. Sci. USA (1992) 89, 6202-6206; Silverman et al., J. Biol. Chem. (1993) 269, 22524-22532; and London, E. (1992) Biochem. Biophys. Acta., 1112, pp.25-51), the translocation domain of Pseudomonas exotoxin type A (Prior et al. Biochemistry (1992) 31, 3555-3559), the translocation domains of anthrax toxin (Blanke et al. Proc. Natl. Acad. Sci. USA (1996) 93, 8437-8442), a variety of fusogenic or hydrophobic peptides of translocating function (Plank et al. J. Biol. Chem. (1994) 269, 12918-12924; and Wagner et al (1992) PNAS, 89, pp.7934-7938), and amphiphilic peptides (Murata et al (1992) Biochem., 31, pp.1986-1992). The Translocation Domain may mirror the Translocation Domain present in a naturally-occurring protein, or may include amino acid variations so long as the variations do not destroy the translocating ability of the Translocation Domain. Particular examples of viral (reference) Translocation Domains suitable for use in the present invention include certain translocating domains of virally expressed membrane fusion proteins. For example, Wagner et al. (1992) and Murata et al. (1992) describe the translocation (i.e. membrane fusion and vesiculation) function of a number of fusogenic and amphiphilic peptides derived from the N-terminal region of influenza virus haemagglutinin. Other virally expressed membrane fusion proteins known to have the desired translocating activity are a translocating domain of a fusogenic peptide of Semliki Forest Virus (SFV), a translocating domain of vesicular stomatitis virus (VSV) glycoprotein G, a translocating domain of SER virus F protein and a translocating domain of Foamy virus envelope glycoprotein. Virally encoded Aspike proteins have particular application in the context of the present invention, for example, the E1 protein of SFV and the G protein of the G protein of VSV. Use of the (reference) Translocation Domains listed in Table (below) includes use of sequence variants thereof. A variant may comprise one or more conservative nucleic acid substitutions and/ or nucleic acid deletions or insertions, with the proviso that the variant possesses the requisite translocating function. A variant may also comprise one or more amino acid substitutions and/ or amino acid deletions, insertions or insertion-deletions (indels), so long as the variant possesses the requisite translocating function. Examples of clostridial neurotoxin HC domain reference sequences include: BoNT/A - N872-L1296 BoNT/B - E859-E1291 BoNT/C1 - N867-E1291 BoNT/D - S863-E1276 BoNT/E - R846-K1252 BoNT/F - K865-E1274 BoNT/G - N864-E1297 TeNT - I880-D1315 For recently-identified BoNT/X, the H _C domain has been reported as corresponding to amino acids 893-1306 thereof, with the domain boundary potentially varying by approximately 25 amino acids (e.g. 868-1306 or 918-1306). Preferably the H _C domain of an engineered clostridial neurotoxin of the invention is a BoNT/X H _C domain. The clostridial neurotoxins described herein may further comprise a translocation facilitating domain. Said domain facilitates delivery of the non-cytotoxic protease into the cytosol of the target cell and are described, for example, in WO 08/008803 and WO 08/008805, each of which is herein incorporated by reference thereto. By way of example, suitable translocation facilitating domains include an enveloped virus fusogenic peptide domain, for example, suitable fusogenic peptide domains include influenzavirus fusogenic peptide domain (eg. influenza A virus fusogenic peptide domain of 23 amino acids), alphavirus fusogenic peptide domain (eg. Semliki Forest virus fusogenic peptide domain of 26 amino acids), vesiculovirus fusogenic peptide domain (eg. vesicular stomatitis virus fusogenic peptide domain of 21 amino acids), respirovirus fusogenic peptide domain (eg. Sendai virus fusogenic peptide domain of 25 amino acids), morbiliivirus fusogenic peptide domain (eg. Canine distemper virus fusogenic peptide domain of 25 amino acids), avulavirus fusogenic peptide domain (eg. Newcastle disease virus fusogenic peptide domain of 25 amino acids), henipavirus fusogenic peptide domain (eg. Hendra virus fusogenic peptide domain of 25 amino acids), metapneumovirus fusogenic peptide domain (eg. Human metapneumovirus fusogenic peptide domain of 25 amino acids) or spumavirus fusogenic peptide domain such as simian foamy virus fusogenic peptide domain; or fragments or variants thereof. By way of further example, a translocation facilitating domain may comprise a clostridial neurotoxin HCN domain or a fragment or variant thereof. In more detail, a clostridial neurotoxin HCN translocation facilitating domain may have a length of at least 200 amino acids, at least 225 amino acids, at least 250 amino acids, at least 275 amino acids. In this regard, a clostridial neurotoxin H _CN translocation facilitating domain preferably has a length of at most 200 amino acids, at most 225 amino acids, at most 250 amino acids, or at most 275 amino acids. Specific (reference) examples include: Botulinum type A neurotoxin - amino acid residues (872-1110) Botulinum type B neurotoxin - amino acid residues (859-1097) Botulinum type C neurotoxin - amino acid residues (867-1111) Botulinum type D neurotoxin - amino acid residues (863-1098) Botulinum type E neurotoxin - amino acid residues (846-1085) Botulinum type F neurotoxin - amino acid residues (865-1105) Botulinum type G neurotoxin - amino acid residues (864-1105) Botulinum type X neurotoxin - amino acid residues (890-1121) Tetanus neurotoxin - amino acid residues (880-1127) The above sequence positions may vary a little according to serotype/ sub-type, and further examples of suitable (reference) clostridial neurotoxin H _CN domains include: Botulinum type A neurotoxin - amino acid residues (874-1110) Botulinum type B neurotoxin - amino acid residues (861-1097) Botulinum type C neurotoxin - amino acid residues (869-1111) Botulinum type D neurotoxin - amino acid residues (865-1098) Botulinum type E neurotoxin - amino acid residues (848-1085) Botulinum type F neurotoxin - amino acid residues (867-1105) Botulinum type G neurotoxin - amino acid residues (866-1105) Tetanus neurotoxin - amino acid residues (882-1127) Any of the above-described facilitating domains may be combined with any of the previously described translocation domain peptides that are suitable for use in the present invention. Thus, by way of example, a non-clostridial facilitating domain may be combined with non-clostridial translocation domain peptide or with clostridial translocation domain peptide. Alternatively, a clostridial neurotoxin HCN translocation facilitating domain may be combined with a non-clostridial translocation domain peptide. Alternatively, a clostridial neurotoxin HCN facilitating domain may be combined or with a clostridial translocation domain peptide, examples of which include: Botulinum type A neurotoxin - amino acid residues (449-1110) Botulinum type B neurotoxin - amino acid residues (442-1097) Botulinum type C neurotoxin - amino acid residues (450-1111) Botulinum type D neurotoxin - amino acid residues (446-1098) Botulinum type E neurotoxin - amino acid residues (423-1085) Botulinum type F neurotoxin - amino acid residues (440-1105) Botulinum type G neurotoxin - amino acid residues (447-1105) Tetanus neurotoxin - amino acid residues (458-1127) In some embodiments the clostridial neurotoxins of the present invention may lack a functional H _C domain of a clostridial neurotoxin. Accordingly, said clostridial neurotoxins are not able to bind rat synaptosomal membranes (via a clostridial H _C component) in binding assays as described in Shone et al. (1985) Eur. J. Biochem. 151, 75-82. The clostridial neurotoxins may preferably lack the last 50 C-terminal amino acids of a clostridial neurotoxin holotoxin. The clostridial neurotoxins may preferably lack the last 100, preferably the last 150, more preferably the last 200, particularly preferably the last 250, and most preferably the last 300 C-terminal amino acid residues of a clostridial neurotoxin holotoxin. Alternatively, the H _C binding activity may be negated/ reduced by mutagenesis – by way of example, referring to BoNT/A for convenience, modification of one or two amino acid residue mutations (W1266 to L and Y1267 to F) in the ganglioside binding pocket causes the HC region to lose its receptor binding function. Analogous mutations may be made to non-serotype A clostridial peptide components, e.g. a construct based on botulinum B with mutations (W1262 to L and Y1263 to F) or botulinum E (W1224 to L and Y1225 to F). Other mutations to the active site achieve the same ablation of HC receptor binding activity, e.g. Y1267S in botulinum type A toxin and the corresponding highly conserved residue in the other clostridial neurotoxins. Details of this and other mutations are described in Rummel et al (2004) (Molecular Microbiol.51:631-634), which is hereby incorporated by reference thereto. The HC peptide of a native clostridial neurotoxin comprises approximately 400-440 amino acid residues, and consists of two functionally distinct domains of approximately 25kDa each, namely the N-terminal region (commonly referred to as the HCN peptide or domain) and the C-terminal region (commonly referred to as the HCC peptide or domain). This fact is confirmed by the following publications, each of which is herein incorporated in its entirety by reference thereto: Umland TC (1997) Nat. Struct. Biol.4: 788-792; Herreros J (2000) Biochem. J.347: 199-204; Halpern J (1993) J. Biol. Chem.268: 15, pp.11188-11192; Rummel A (2007) PNAS 104: 359-364; Lacey DB (1998) Nat. Struct. Biol.5: 898-902; Knapp (1998) Am. Cryst. Assoc. Abstract Papers 25: 90; Swaminathan and Eswaramoorthy (2000) Nat. Struct. Biol.7: 1751-1759; and Rummel A (2004) Mol. Microbiol.51(3), 631-643. Moreover, it has been well documented that the C-terminal region (HCC), which constitutes the C-terminal 160-200 amino acid residues, is responsible for binding of a clostridial neurotoxin to its natural cell receptors, namely to nerve terminals at the neuromuscular junction - this fact is also confirmed by the above publications. Thus, reference throughout this specification to a clostridial heavy-chain lacking a functional heavy chain H _C peptide (or domain) such that the heavy-chain is incapable of binding to cell surface receptors to which a native clostridial neurotoxin binds means that the clostridial heavy-chain simply lacks a functional H _CC peptide. In other words, the H _CC peptide region may be either partially or wholly deleted, or otherwise modified (e.g. through conventional chemical or proteolytic treatment) to inactivate its native binding ability for nerve terminals at the neuromuscular junction. Thus, a clostridial neurotoxin H _N peptide of the present invention may be C-terminally extended, i.e. it may be associated with all or part of a clostridial neurotoxin H _C domain, e.g. the H _CN , H _CC or H _C domain. References herein to a clostridial neurotoxin H _N peptide of the present invention encompass such C-terminally extended H _N peptides, which comprise one or more amino acid residues from a clostridial neurotoxin H _C domain. Alternatively, a clostridial neurotoxin H _N peptide of the present invention may not be associated with (or lack) all or part of a clostridial neurotoxin H _C domain, e.g. the H _CN , H _CC or H _C domain. Typically if a clostridial neurotoxin of the invention or a clostridial neurotoxin H _N peptide of the present invention lacks all or part of a C-terminal peptide portion (H _CC ) of a clostridial neurotoxin it thus lacks the HC binding function of native clostridial neurotoxin. By way of example, a C-terminally extended clostridial HN peptide may lack the C-terminal 40 amino acid residues, or the C-terminal 60 amino acid residues, or the C-terminal 80 amino acid residues, or the C-terminal 100 amino acid residues, or the C-terminal 120 amino acid residues, or the C-terminal 140 amino acid residues, or the C-terminal 150 amino acid residues, or the C- terminal 160 amino acid residues of a clostridial neurotoxin heavy-chain. Alternatively, the clostridial HN peptide of the present invention may lack the entire C-terminal peptide portion (HCC) of a clostridial neurotoxin and thus lacks the HC binding function of native clostridial neurotoxin. By way of example, the clostridial HN peptide may lack the C-terminal 165 amino acid residues, or the C-terminal 170 amino acid residues, or the C-terminal 175 amino acid residues, or the C-terminal 180 amino acid residues, or the C-terminal 185 amino acid residues, or the C-terminal 190 amino acid residues, or the C-terminal 195 amino acid residues of a clostridial neurotoxin heavy-chain. By way of further example, the clostridial HN peptide of the present invention lacks a clostridial HCC reference sequence selected from the group consisting of: Botulinum type A neurotoxin - amino acid residues (Y1111-L1296) Botulinum type B neurotoxin - amino acid residues (Y1098-E1291) Botulinum type C neurotoxin - amino acid residues (Y1112-E1291) Botulinum type D neurotoxin - amino acid residues (Y1099-E1276) Botulinum type E neurotoxin - amino acid residues (Y1086-K1252) Botulinum type F neurotoxin - amino acid residues (Y1106-E1274) Botulinum type G neurotoxin - amino acid residues (Y1106-E1297) Botulinum type X neurotoxin - amino acid residues (Y1122-D1306) Tetanus neurotoxin - amino acid residues (Y1128-D1315). The above-identified reference sequences should be considered a guide as slight variations may occur according to sub-serotypes. The present invention is suitable for application to many different varieties of clostridial neurotoxin. Thus, in the context of the present invention, the term “clostridial neurotoxin” embraces toxins produced by C. botulinum (botulinum neurotoxin serotypes A, B, C1, D, E, F, G, H, and X), C. tetani (tetanus neurotoxin), C. butyricum (botulinum neurotoxin serotype E), and C. baratii (botulinum neurotoxin serotype F), as well as modified clostridial neurotoxins or derivatives derived from any of the foregoing. The term “clostridial neurotoxin” also embraces botulinum neurotoxin serotype H. In some preferred embodiments, the clostridial neurotoxin is BoNT/A, more preferably BoNT/A ₁ . In other preferred embodiments, the clostridial neurotoxin is BoNT/X. Botulinum neurotoxin (BoNT) is produced by C. botulinum in the form of a large protein complex, consisting of BoNT itself complexed to a number of accessory proteins. There are at present nine different classes of botulinum neurotoxin, namely: botulinum neurotoxin serotypes A, B, C1, D, E, F, G, H, and X all of which share similar structures and modes of action. Different BoNT serotypes can be distinguished based on inactivation by specific neutralising anti-sera, with such classification by serotype correlating with percentage sequence identity at the amino acid level. BoNT proteins of a given serotype are further divided into different subtypes on the basis of amino acid percentage sequence identity. BoNTs are absorbed in the gastrointestinal tract, and, after entering the general circulation, bind to the presynaptic membrane of cholinergic nerve terminals and prevent the release of their neurotransmitter acetylcholine. BoNT/B, BoNT/D, BoNT/F and BoNT/G cleave synaptobrevin/vesicle-associated membrane protein (VAMP); BoNT/C1, BoNT/A and BoNT/E cleave the synaptosomal-associated protein of 25 kDa (SNAP-25); and BoNT/C1 cleaves syntaxin. BoNT/X has been found to cleave SNAP-25, VAMP1, VAMP2, VAMP3, VAMP4, VAMP5, Ykt6, and syntaxin 1. Tetanus toxin is produced in a single serotype by C. tetani. C. butyricum produces BoNT/E, while C. baratii produces BoNT/F. The term “clostridial neurotoxin” is also intended to embrace modified clostridial neurotoxins and derivatives thereof, including but not limited to those described below. A modified clostridial neurotoxin or derivative may contain one or more amino acids that has been modified as compared to the native (unmodified) form of the clostridial neurotoxin, or may contain one or more inserted amino acids that are not present in the native (unmodified) form of the clostridial neurotoxin. By way of example, a modified clostridial neurotoxin may have modified amino acid sequences in one or more domains relative to the native (unmodified) clostridial neurotoxin sequence. Such modifications may modify functional aspects of the toxin, for example biological activity or persistence. Thus, a clostridial neurotoxin of the invention may be a modified clostridial neurotoxin, or a modified clostridial neurotoxin derivative, or a clostridial neurotoxin derivative. In particular, an engineered clostridial neurotoxin of the invention may be an engineered modified clostridial neurotoxin, or an engineered modified clostridial neurotoxin derivative, or an engineered clostridial neurotoxin derivative. A modified clostridial neurotoxin may have one or more modifications in the amino acid sequence of the heavy chain (such as a modified H _C domain), wherein said modified heavy chain binds to target nerve cells with a higher or lower affinity than the native (unmodified) clostridial neurotoxin. Such modifications in the H _C domain can include modifying residues in the ganglioside binding site of the H _C domain or in the protein (SV2 or synaptotagmin) binding site that alter binding to the ganglioside receptor and/or the protein receptor of the target nerve cell. Examples of such modified clostridial neurotoxins are described in WO 2006/027207 and WO 2006/114308, both of which are hereby incorporated by reference in their entirety. Most preferably, a BoNT/B HC domain further comprises at least one amino acid residue substitution, insertion, indel or deletion in the HCC subdomain which has the effect of increasing the binding affinity of BoNT/B neurotoxin for human Syt II as compared to the natural BoNT/B sequence. Suitable amino acid residue substitutions, insertions, indels or deletions in the BoNT/B HCC subdomain have been disclosed in WO 2013/180799 and in WO 2016/154534 (both herein incorporated by reference). A suitable amino acid residue substitution, insertion, indel or deletion in the BoNT/B HCC subdomain may include substitution mutations selected from the group consisting of: V1118M; Y1183M; E1191M; E1191I; E1191Q; E1191T; S1199Y; S1199F; S1199L; S1201V; E1191C, E1191V, E1191L, E1191Y, S1199W, S1199E, S1199H, W1178Y, W1178Q, W1178A, W1178S, Y1183C, Y1183P and combinations thereof. A suitable amino acid residue substitution, insertion, indel or deletion in the BoNT/B HCC subdomain may further include combinations of two substitution mutations selected from the group consisting of: E1191M and S1199L, E1191M and S1199Y, E1191M and S1199F, E1191Q and S1199L, E1191Q and S1199Y, E1191Q and S1199F, E1191M and S1199W, E1191M and W1178Q, E1191C and S1199W, E1191C and S1199Y, E1191C and W1178Q, E1191Q and S1199W, E1191V and S1199W, E1191V and S1199Y, or E1191V and W1178Q. A suitable amino acid residue substitution, insertion, indel or deletion in the BoNT/B H _CC subdomain may also include a combination of three substitution mutations which are E1191M, S1199W and W1178Q. Preferably, the amino acid residue substitution, insertion, indel or deletion in the BoNT/B H _CC subdomain includes a combination of two substitution mutations which are E1191M and S1199Y. Such modifications are present in chimeric clostridial neurotoxin of SEQ ID NO: 136. E1191M may correspond to position 1204 of SEQ ID NO: 136and S1199Y may correspond to position 1212. Thus, SEQ ID NO: 136may comprise 1204M and 1212Y. The modification may be a modification when compared to unmodified BoNT/B shown as SEQ ID NO: 99, wherein the amino acid residue numbering is determined by alignment with SEQ ID NO: 99. As the presence of a methionine residue at position 1 of SEQ ID NO: 99 (as well as the SEQ ID NOs corresponding to other clostridial neurotoxin polypeptides described herein, including chimeric clostridial neurotoxin polypeptides) is optional, the skilled person will take the presence/absence of the methionine residue into account when determining amino acid residue numbering. For example, where SEQ ID NO: 99 includes a methionine, the position numbering will be as defined above (e.g. E1191 will be E1191 of SEQ ID NO: 99). Alternatively, where the methionine is absent from SEQ ID NO: 99 the amino acid residue numbering should be modified by -1 (e.g. E1191 will be E1190 of SEQ ID NO: 99). Accordingly, an initial methionine amino acid residue of a polypeptide sequence of the chimeric clostridial neurotoxin may be optional or absent. Similar considerations apply when the methionine at position 1 of the other polypeptide sequences described herein is present/absent, and the skilled person will readily determine the correct amino acid residue numbering using techniques routine in the art. Alignment may be carried out using any of the methods described herein for determining sequence homology and/or % sequence identity. A modified clostridial neurotoxin may have one or more modifications in the amino acid sequence of the light chain, for example modifications in the substrate binding or catalytic domain which may alter or modify the SNARE protein specificity of the modified L-chain. Examples of such modified clostridial neurotoxins are described in WO 2010/120766 and US 2011/0318385, both of which are hereby incorporated by reference in their entirety. A modified clostridial neurotoxin may comprise one or more modifications that increases or decreases the biological activity and/or the biological persistence of the modified clostridial neurotoxin. For example, a modified clostridial neurotoxin may comprise a leucine- or tyrosine-based motif, wherein said motif increases or decreases the biological activity and/or the biological persistence of the modified clostridial neurotoxin. Suitable leucine-based motifs include xDxxxLL (SEQ ID NO: 144), xExxxLL (SEQ ID NO: 145), xExxxIL (SEQ ID NO: 146), and xExxxLM (SEQ ID NO: 147) (wherein x is any amino acid). Suitable tyrosine-based motifs include Y-x-x-Hy (wherein Hy is a hydrophobic amino acid). Examples of modified clostridial neurotoxins comprising leucine- and tyrosine-based motifs are described in WO 2002/008268, which is hereby incorporated by reference in its entirety. The term “clostridial neurotoxin” is intended to embrace hybrid and chimeric clostridial neurotoxins. A hybrid clostridial neurotoxin comprises at least a portion of a light chain from one clostridial neurotoxin or subtype thereof, and at least a portion of a heavy chain from another clostridial neurotoxin or clostridial neurotoxin subtype. A hybrid clostridial neurotoxin may contain the entire light chain from one clostridial neurotoxin subtype and the heavy chain from another clostridial neurotoxin subtype. A chimeric clostridial neurotoxin may contain a portion (e.g. the binding domain) of the heavy chain of one clostridial neurotoxin subtype, with another portion of the heavy chain being from another clostridial neurotoxin subtype. A chimeric clostridial neurotoxin, particularly a chimeric BoNT, may be defined in terms of the serotype or sub-serotype of the four main domains of the neurotoxin: L-chain, H _N , H _CN and H _CC (as defined herein). For example, the (pre-engineering) LH _N /A1-H _C B1 chimera of SEQ ID NO: 136 may be described as an AABB chimera. Similarly or alternatively, the therapeutic element may comprise light chain portions from different clostridial neurotoxins. Such hybrid or chimeric clostridial neurotoxins are useful, for example, as a means of delivering the therapeutic benefits of such clostridial neurotoxins to patients who are immunologically resistant to a given clostridial neurotoxin subtype, to patients who may have a lower than average concentration of receptors to a given clostridial neurotoxin heavy chain binding domain, or to patients who may have a protease-resistant variant of the membrane or vesicle toxin substrate (e.g., SNAP-25, VAMP and syntaxin). Hybrid and chimeric clostridial neurotoxins are described in US 8,071,110, which publication is hereby incorporated by reference in its entirety. Thus, a clostridial neurotoxin of the invention may be a hybrid clostridial neurotoxin, or a chimeric clostridial neurotoxin. In particular, an engineered clostridial neurotoxin of the invention may be an engineered hybrid clostridial neurotoxin, or an engineered chimeric clostridial neurotoxin. In some preferred embodiments, a clostridial neurotoxin is BoNT/A comprising at least one domain from a non-BoNT/A clostridial neurotoxin (e.g. a BoNT/A hybrid or chimera). For example, a clostridial neurotoxin of the invention (comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/A L-chain and a non-BoNT/A HN and HC domain; ii. A BoNT/A HN domain and a non-BoNT/A L-chain and HC domain iii. A BoNT/A HC domain and a non-BoNT/A L-chain and HN domain; iv. A BoNT/A L-chain and HN domain and a non-BoNT/A HC domain v. A BoNT/A L-chain and HC domain and a non-BoNT/A HN domain; or vi. A BoNT/A HN domain and HC domain and a non-BoNT/A L-chain. By way of non-limiting example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) comprises a BoNT/A L-chain and H _N domain and a BoNT/B H _C domain (such as LH _N /A1-H _C /B1). An exemplary non-engineered LH _N /A1-H _C B1 chimera that may be modified to comprises one or more exogenous protease cleavage site according to the invention is given in SEQ ID NO: 136. Exemplary engineered forms of the LH _N /A1-H _C B1 chimera of SEQ ID NO: 136 are given in SEQ ID NOs: 155, 157 and 159. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a BoNT/C1 H _C domain. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a BoNT/D H _C domain. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a BoNT/E H _C domain. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a BoNT/F H _C domain. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a BoNT/G H _C domain. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a BoNT/X H _C domain. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and H _N domain and a TeNT H _C domain. For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/B L-chain and a non-BoNT/B HN and HC domain; ii. A BoNT/B HN domain and a non-BoNT/B L-chain and HC domain iii. A BoNT/B HC domain and a non-BoNT/B L-chain and HN domain; iv. A BoNT/B L-chain and HN domain and a non-BoNT/B HC domain v. A BoNT/B L-chain and HC domain and a non-BoNT/B HN domain; or vi. A BoNT/B HN domain and HC domain and a non-BoNT/B L-chain. For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/C1 L-chain and a non-BoNT/C1 HN and HC domain; ii. A BoNT/C1 HN domain and a non-BoNT/C1 L-chain and HC domain iii. A BoNT/C1 HC domain and a non-BoNT/C1 L-chain and HN domain; iv. A BoNT/C1 L-chain and HN domain and a non-BoNT/C1 HC domain v. A BoNT/C1 L-chain and HC domain and a non-BoNT/C1 HN domain; or vi. A BoNT/C1 HN domain and HC domain and a non-BoNT/C1 L-chain. Non-limiting examples include BoNT/C1 chimeras where the non-BoNT/C1 element is from a BoNT/D (i.e. BoNT/CD chimeras). For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/D L-chain and a non-BoNT/D H _N and H _C domain; ii. A BoNT/D H _N domain and a non-BoNT/D L-chain and H _C domain iii. A BoNT/D H _C domain and a non-BoNT/D L-chain and H _N domain; iv. A BoNT/D L-chain and H _N domain and a non-BoNT/D H _C domain v. A BoNT/D L-chain and H _C domain and a non-BoNT/D H _N domain; or vi. A BoNT/D H _N domain and H _C domain and a non-BoNT/D L-chain. Non-limiting examples include BoNT/D chimeras where the non-BoNT/D element is from BoNT/C1 (i.e. BoNT/DC1 chimeras). For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/E L-chain and a non-BoNT/E H _N and H _C domain; ii. A BoNT/E H _N domain and a non-BoNT/E L-chain and H _C domain iii. A BoNT/E H _C domain and a non-BoNT/E L-chain and H _N domain; iv. A BoNT/E L-chain and H _N domain and a non-BoNT/E H _C domain v. A BoNT/E L-chain and H _C domain and a non-BoNT/E H _N domain; or vi. A BoNT/E H _N domain and H _C domain and a non-BoNT/E L-chain. For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/F L-chain and a non-BoNT/F HN and HC domain; ii. A BoNT/F HN domain and a non-BoNT/F L-chain and HC domain iii. A BoNT/F HC domain and a non-BoNT/F L-chain and HN domain; iv. A BoNT/F L-chain and HN domain and a non-BoNT/F HC domain v. A BoNT/F L-chain and HC domain and a non-BoNT/F HN domain; or vi. A BoNT/F HN domain and HC domain and a non-BoNT/F L-chain. For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/G L-chain and a non-BoNT/G HN and HC domain; ii. A BoNT/G HN domain and a non-BoNT/G L-chain and HC domain iii. A BoNT/G HC domain and a non-BoNT/G L-chain and HN domain; iv. A BoNT/G L-chain and HN domain and a non-BoNT/G HC domain v. A BoNT/G L-chain and HC domain and a non-BoNT/G HN domain; or vi. A BoNT/G HN domain and HC domain and a non-BoNT/G L-chain. For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A BoNT/X L-chain and a non-BoNT/X HN and HC domain; ii. A BoNT/X HN domain and a non-BoNT/X L-chain and HC domain iii. A BoNT/X HC domain and a non-BoNT/X L-chain and HN domain; iv. A BoNT/X L-chain and H _N domain and a non-BoNT/X H _C domain v. A BoNT/X L-chain and H _C domain and a non-BoNT/X H _N domain; or vi. A BoNT/X H _N domain and H _C domain and a non-BoNT/X L-chain. For example, a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin comprising one or more exogenous protease cleavage site) may comprise: i. A TeNT L-chain and a non-TeNT H _N and H _C domain; ii. A TeNT H _N domain and a non-TeNT L-chain and H _C domain iii. A TeNT H _C domain and a non-TeNT L-chain and H _N domain; iv. A TeNT L-chain and H _N domain and a non-TeNT H _C domain v. A TeNT L-chain and H _C domain and a non-TeNT H _N domain; or vi. A TeNT H _N domain and H _C domain and a non-TeNT L-chain. The term “clostridial neurotoxin” may also embrace newly discovered botulinum neurotoxin and botulinum neurotoxin-like protein family members expressed by non-clostridial microorganisms, such as the Enterococcus encoded toxin which has closest sequence identity to BoNT/X, the Weissella oryzae encoded toxin called BoNT/Wo (NCBI Ref Seq: WP_027699549.1), which cleaves VAMP2 at W89-W90, the Enterococcus faecium encoded toxin (GenBank: OTO22244.1), which cleaves VAMP2 and SNAP25, the Chryseobacterium pipero encoded toxin (NCBI Ref. Seq: WP_034687872.1) and the mosquito BoNT-like protein PMP1 (NCBI Ref. Seq: QEZ70852.1). The term “clostridial neurotoxin” is intended to embrace re-targeted clostridial neurotoxins. In a re-targeted clostridial neurotoxin, the clostridial neurotoxin is modified to include an exogenous ligand (i.e. not derived from a clostridial neurotoxin) known as a Targeting Moiety (TM). The TM is selected to provide binding specificity for a desired target cell, and as part of the re-targeting process the native binding portion of the clostridial neurotoxin (e.g. the HC domain, or the HCC domain) may be removed. Re-targeting technology is described, for example, in: EP-B-0689459; WO 1994/021300; EP-B-0939818; US 6,461,617; US 7,192,596; WO 1998/007864; EP-B-0826051; US 5,989,545; US 6,395,513; US 6,962,703; WO 1996/033273; EP-B-0996468; US 7,052,702; WO 1999/017806; EP-B- 1107794; US 6,632,440; WO 2000/010598; WO 2001/21213; WO 2006/059093; WO 2000/62814; WO 2000/04926; WO 1993/15766; WO 2000/61192; and WO 1999/58571; all of which are hereby incorporated by reference in their entirety. Thus, a clostridial neurotoxin of the invention may be a re-targeted clostridial neurotoxin. In particular, an engineered clostridial neurotoxin of the invention may be an engineered re-targeted clostridial neurotoxin. The engineered re-targeted clostridial neurotoxins of the invention may comprise TM that are presented at the N- or C-terminus of the single-chain neurotoxin, or the TM may be presented centrally within the single-chain neurotoxin. In some preferred embodiments, the engineered re-targeted clostridial neurotoxins of the invention may comprise TM that are presented at the N- or C-terminus of the single-chain neurotoxin. Engineering re-targeted clostridial neurotoxins may allow for the use of TM that are susceptible to cleavage by proteases conventionally used to activate recombinantly produced re-targeted clostridial neurotoxins, such as trypsin, Lys-C and/or BoNT hydrolase. Thus, engineering re-targeted clostridial neurotoxins to include one or more exogenous protease activation site according to the invention may allow for improvements in stability compared to a corresponding re-targeted clostridial neurotoxins which is activated by a conventional activating protease such as Lys-C, trypsin and/or BoNT hydrolase. In some preferred embodiments, an engineered re-targeted clostridial neurotoxin comprises a BoNT/A light chain (LC/A) and/or a BoNT/A translocation domain (H _N /A), particularly preferred both a LC/A and H _N /A, optionally wherein in the pre-engineered re- targeted clostridial neurotoxin the endogenous BoNT/A activation loop has been replaced with an endogenous BoNT/C activation loop. Non-limiting examples of engineered re-targeted clostridial neurotoxins, may comprise SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. In some particularly preferred embodiments, an engineered re-targeted clostridial neurotoxin comprises a BoNT/X light chain (LC/X) and/or a BoNT/X translocation domain (HN/X), particularly preferred both a LC/X and HN/X, optionally wherein in the pre-engineered re-targeted clostridial neurotoxin the endogenous BoNT/X activation loop has been replaced with an endogenous BoNT/C activation loop. Such engineered re-targeted BoNT/X are particularly preferred. Non-limiting examples of engineered re-targeted clostridial neurotoxins, may comprise SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The clostridial neurotoxin of the present invention (e.g. an engineered clostridial neurotoxin) may lack a functional HC domain of a clostridial neurotoxin and also lack any functionally equivalent TM. Accordingly, said polypeptides lack the natural binding function of a clostridial neurotoxin and are not able to bind rat synaptosomal membranes (via a clostridial HC component, or via any functionally equivalent TM) in binding assays as described in Shone et al. (1985) Eur. J. Biochem.151, 75-82. Preferably the TM is not a Wheat Germ Agglutinin (WGA) peptide. Thus, in some preferred embodiments the clostridial neurotoxin is a re- targeted clostridial neurotoxin in which an endogenous H _C or H _CC of a clostridial neurotoxin is replaced by an exogenous TM. Particularly preferred are embodiments in which the engineered clostridial neurotoxin is a re-targeted clostridial neurotoxin in which an endogenous H _C or H _CC of a clostridial neurotoxin is replaced by an exogenous TM. A clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) may comprise an LH _N polypeptide (e.g. an engineered LH _N polypeptide), i.e. a polypeptide comprising or consisting of a clostridial L-chain and a clostridial H _N domain, as defined herein. A clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) may comprise an LH _N polypeptide (e.g. an engineered LH _N polypeptide) and a targeting moiety (TM). The present invention also embraces clostridial neurotoxins that have an additional non-native protease cleavage site. Such a site will require an exogenous protease for cleavage, which allows for improved control over the timing and location of cleavage events. Additional non-native protease cleavage sites that may be employed in clostridial neurotoxins include: TEV(Tobacco Etch virus) (ENLYFQ↓G) (SEQ ID NO: 148) PreScission (LEVLFQ↓GP) (SEQ ID NO: 149). Additional protease cleavage sites include recognition sequences that are cleaved by a non-cytotoxic protease, for example by the light chain of a clostridial neurotoxin. These include the SNARE (e.g. SNAP-25, syntaxin, VAMP) protein recognition sequences that are cleaved by non-cytotoxic proteases such as the light chain of a clostridial neurotoxin. Clostridial neurotoxins comprising non-native protease cleavage sites are described in US 7,132,259, EP 1206554-B2 and US 2007/0166332, all of which are hereby incorporated by reference in their entirety. Also embraced by the term protease cleavage site is an intein, which is a self-cleaving sequence. The self-splicing reaction is controllable, for example by varying the concentration of reducing agent present. The present invention also embraces clostridial neurotoxins comprising a “destructive cleavage site”. In said clostridial neurotoxins, a non-native protease cleavage site is incorporated into the clostridial neurotoxin, at a location chosen such that cleavage at said site will decrease the activity of, or inactivate, the clostridial neurotoxin. The destructive protease cleavage site can be susceptible to cleavage by a local protease, in the event that the clostridial neurotoxin, following administration, migrates to a non-target location. Suitable non- native protease cleavage sites include those described above. Clostridial neurotoxins comprising a destructive cleavage site are described in WO 2010/094905 and WO 2002/044199, both of which are hereby incorporated by reference in their entirety. The clostridial neurotoxins (e.g. engineered clostridial neurotoxins) of the present invention, especially the light chain component thereof, may be PEGylated – this may help to increase stability, for example duration of action of the light chain component. PEGylation is particularly preferred when the light chain comprises a BoNT/A, B or C1 protease. PEGylation preferably includes the addition of PEG to the N-terminus of the light chain component. By way of example, the N-terminus of a light chain may be extended with one or more amino acid (e.g. cysteine) residues, which may be the same or different. One or more of said amino acid residues may have its own PEG molecule attached (e.g. covalently attached) thereto. An example of this technology is described in WO2007/104567, which is hereby incorporated by reference in its entirety. A chimeric clostridial neurotoxin of the invention may not comprise a therapeutic or diagnostic agent (e.g. a nucleic acid, protein, peptide or small molecule therapeutic or diagnostic agent) additional to the light-chain and heavy-chain. For example, in one embodiment, the chimeric clostridial neurotoxin may not comprise a covalently or non- covalently associated therapeutic or diagnostic agent. Thus, a chimeric clostridial neurotoxin of the invention preferably does not function as a delivery vehicle for a further therapeutic or diagnostic agent. In embodiments where a chimeric clostridial neurotoxin described herein has a tag for purification (e.g. a His-tag) and/or a linker, said tag and/or linker are optional. The clostridial neurotoxins (e.g. engineered clostridial neurotoxins) of the present invention may be free from the complexing proteins that are present in a naturally occurring clostridial neurotoxin complex. The clostridial neurotoxins (e.g. engineered clostridial neurotoxins) of the present invention can be produced using recombinant nucleic acid technologies. Thus, in an engineered clostridial neurotoxin (as described above) may be a recombinant engineered clostridial neurotoxin. A single-chain clostridial neurotoxin (as described herein) may be a recombinant single-chain neurotoxin. Tolerance (i.e. a reduction in the number and/or severity of any side effects) to an engineered clostridial neurotoxin of the invention may be increased compared with the tolerance to the corresponding (pre-engineering) clostridial neurotoxin. In particular, tolerance to an engineered clostridial neurotoxin of the invention may be increased compared with the tolerance to the corresponding (pre-engineering) clostridial neurotoxin when the pre- engineering clostridial neurotoxin is administered (e.g. in di-chain form). An engineered clostridial neurotoxin of the invention may have equivalent or increased potency compared with the potency of the corresponding (pre-engineering) clostridial neurotoxin. In particular, potency of an engineered clostridial neurotoxin of the invention may be equivalent to or increased compared with the potency of the corresponding (pre- engineering) clostridial neurotoxin when the pre-engineering clostridial neurotoxin is administered in di-chain form. The term “equivalent potency” as used herein means that an engineered clostridial neurotoxin has a potency of at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, up to about 100% of the potency of the corresponding (pre-engineering) clostridial neurotoxin. Preferably “equivalent potency” as used herein means that an engineered clostridial neurotoxin has a potency of at least about 95%, at least about 99%, at least about 100%, at least about 101%, up to about 105% of the potency of the corresponding (pre-engineering) clostridial neurotoxin. The term “increased potency” as used herein means that an engineered clostridial neurotoxin has a potency of at least about 10%, at least about 15%, at least about 20%, at least about 25% greater potency compared with the potency of the corresponding (pre-engineering) clostridial neurotoxin. Potency may be measured using any appropriate assay, conventional examples of which are described herein. An engineered clostridial neurotoxin of the invention typically has an improved safety profile and/or therapeutic window compared with the safety profile and/or therapeutic window of the corresponding (pre-engineering) clostridial neurotoxin. Without being bound by theory, this may be by virtue of its improved tolerance and/or equivalent or increased potency. In particular, an engineered clostridial neurotoxin of the invention may have an improved safety profile and/or therapeutic window compared with the safety profile and/or therapeutic window of the corresponding (pre-engineering) clostridial neurotoxin when the pre-engineering clostridial neurotoxin is administered (e.g. in di-chain form). One way in which these advantageous properties (which represent an increase in the therapeutic index) may be defined is in terms of the Safety Ratio (for clinical applications) or Tolerance Index (TI, in animal models, which may be calculated as described below) of the engineered clostridial toxin. In this regard, undesired effects of a clostridial neurotoxin (such as those caused by diffusion of the neurotoxin away from the site of administration) can be assessed experimentally by measuring percentage bodyweight loss in a relevant animal model (e.g. a mouse, where loss of bodyweight is detected within seven days of administration). Desired on-target effects of a clostridial toxin can be assessed experimentally by any appropriate technique, depending on the target cell of interest. Suitable assays are known in the art and it would be routine for one of ordinary skill to select an appropriate assay for a given target cell type. For clostridial neurotoxins of the invention which target motor neurons, a Digital Abduction Score (DAS) assay, a measurement of muscle paralysis, may be used. The DAS assay may be performed by injection of 20μl of (engineered) clostridial toxin, formulated in Gelatin Phosphate Buffer, into the mouse gastrocnemius/soleus complex, followed by assessment of Digital Abduction Score using the method of Aoki (Aoki KR, Toxicon 39: 1815-1820; 2001). In the DAS assay, mice are suspended briefly by the tail in order to elicit a characteristic startle response in which the mouse extends its hind limbs and abducts its hind digits. Following clostridial toxin injection, the varying degrees of digit abduction are scored on a five-point scale (0=normal to 4=maximal reduction in digit abduction and leg extension). For clostridial neurotoxins of the invention which target other subtypes of neurones, any appropriate assay known in the art may be used. SNARE cleavage assays may also be used to assess the activity of engineered clostridial neurotoxins of the invention, examples of which are well-described in the art (e.g. Western blot). Assays to detect and/or quantify the effect of an engineered clostridial neurotoxin on the release of a maker signalling molecule may also be used. The specific marker signally molecule may be selected depending on the cell type(s) targeted by the engineered clostridial neurotoxins. For example, the signalling molecule may be a hormone, substance P, CGRP, glutamate, glycine, depending on whether cells involved with hormone secretion or pain-sensing neurons are targeted. For the treatment of pain, animal studies may be used to assess if there is a greater tolerance to a noxious stimulus. Typical in vivo assays will measure different types of pain (e.g., mechanical, cold, heat) and the readout could be behavioural (e.g., licking/biting the treated site or withdrawal from the noxious stimulus) or may involve the use of the Von Frey test. Any appropriate nociception test may be used, and examples of such tests are well- known in the art. The Safety Ratio or TI of a clostridial neurotoxin may then be expressed as the ratio between the amount of toxin required for a 10% drop in a bodyweight (measured at peak effect within the first seven days after dosing in a mouse) and the amount of toxin required for a DAS score of 2. High Safety Ratio or TI scores are therefore desired, and indicate a toxin that is able to effectively paralyse a target muscle with little undesired off-target effects. An engineered toxin of the present invention may have a Safety Ratio and/or TI that is higher than the Safety Ratio and/or TI of an equivalent unmodified (pre-engineering) single-chain clostridial neurotoxin. The calculation for TI may vary depending on the experimental model used. For example, in a DAS mouse model, an engineered clostridial toxin of the present invention has a TI of at least 8 (for example, at least 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 or 50), wherein TI is calculated as: dose of toxin required for -10% bodyweight change (pg/mouse) divided by DAS ED50 (pg/mouse) [ED50 = dose required to produce a DAS score of 2]. For clinical use a Safety Ratio may be calculated. Any clostridial neurotoxin as described herein may be engineered according to the invention to comprise any exogenous protease cleavage site, exogenous activation loop comprising one or more exogenous protease cleavage site or modified BoNT/C (BoNT/C1) activation loop as described herein. The invention provides a nucleic acid (for example, a DNA or RNA) comprising a nucleic acid sequence encoding a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) as described herein. The nucleic acid sequence may be prepared as part of an expression vector in which the nucleic acid is operably linked to a promoter. Preferably, the nucleic acid may be prepared as part of a DNA expression vector comprising a promoter and a terminator. Preferably the vector has a promoter selected from: Promoter Induction Agent Typical Induction Condition Tac (hybrid) IPTG 0.2 mM (0.05-2.0mM) AraBAD L-arabinose 0.2% (0.002-0.4%) T7-lac operator IPTG 0.2 mM (0.05-2.0mM) Alternatively, a promoter may preferably be selected from: Promoter Induction Agent Typical Induction Condition Tac (hybrid) IPTG 0.2 mM (0.05-2.0mM) AraBAD L-arabinose 0.2% (0.002-0.4%) T7-lac operator IPTG 0.2 mM (0.05-2.0mM) T5-lac operator IPTG 0.2 mM (0.05-2.0mM) The nucleic acid molecules of the invention may be made using any suitable process known in the art. Thus, the nucleic acid molecules may be made using chemical synthesis techniques. Alternatively, the nucleic acid molecules of the invention may be made using molecular biology techniques. The nucleic acid molecules and expression vectors of the present invention may be preferably designed in silico, and then synthesised by conventional synthesis techniques, including conventional DNA synthesis techniques. The above-mentioned nucleic acid sequence information is optionally modified for codon-biasing according to the ultimate host cell (e.g. E. coli) expression system that is to be employed. The present invention provides a nucleotide sequence encoding an engineered clostridial neurotoxin of the present invention. The nucleotide sequence of the invention encodes a polypeptide comprising one or more exogenous protease cleavage site as described herein. The nucleotide sequence may comprise a sequence having at least 70% sequence identity to SEQ ID NO: 154, 156, 158, 160, 162 or 164. The nucleotide sequence may comprise a sequence having at least 80% or 90% sequence identity to SEQ ID NO: 154, 156, 158, 160, 162 or 164. Preferably the nucleotide sequence comprises (more preferably consists of) SEQ ID NO: 154, 156, 158, 160, 162 or 164. The nucleotide sequence may encode an engineered clostridial neurotoxin comprising or consisting of an amino acid sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 155, 157, 159, 161, 163, 165, 166, 167 or 168. The nucleotide sequence may encode an engineered clostridial neurotoxin comprising or consisting of an amino acid sequence having at least 80% or 90% sequence identity to one or more of SEQ ID NOs: 155, 157, 159, 161, 163, 165, 166, 167 or 168. Preferably the nucleotide sequence encode an engineered clostridial neurotoxin comprising (more preferably consisting of) any one of SEQ ID NOs: 155, 157, 159, 161, 163, 165, 166, 167 or 168 The engineered clostridial neurotoxin may be encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease cleavage site or a modified BoNT/C activation loop as defined herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be encoded by a nucleic acid comprising or consisting of a nucleotide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease cleavage site or a modified BoNT/C activation loop as defined herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may encoded by a nucleic acid comprising or consisting of the nucleotide sequence of SEQ ID NO: 175, wherein SEQ ID NO: 176 within SEQ ID NO: 175 is replaced by a nucleotide sequence encoding at least one exogenous protease cleavage site or a modified BoNT/C activation loop as defined herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. Alternatively or in addition, the engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin comprising or consisting of a polypeptide sequence having (i) at least 70% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 70% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin comprising or consisting of a polypeptide sequence having (i) at least 80% or 90% sequence identity to SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) at least 80% or 90% identity to SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin comprising or consisting of (i) the polypeptide sequence of SEQ ID NO: 150, wherein SEQ ID NO: 2 within SEQ ID NO: 150 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65; or (ii) the polypeptide sequence of SEQ ID NO: 152, wherein SEQ ID NO: 2 within SEQ ID NO: 152 has been replaced by one or more exogenous protease cleavage site and/or modified BoNT/C activation loop as described herein, wherein the one or more exogenous protease site is preferably selected from one or more SEQ ID NOs: 15, 33 or 25, and/or the modified BoNT/C activation loop is preferably selected from one or more SEQ ID NOs: 57, 63 and/or 65. The terms “nucleotide sequence” and “nucleic acid” and “polynucleotide” are used synonymously herein. Preferably the nucleotide sequence is a DNA sequence. The invention provides a method of producing a single-chain (engineered) clostridial neurotoxin protein having a light chain and a heavy chain, the method comprising expressing a polynucleotide or expression vector described herein in a suitable host cell, and recovering the expressed engineered clostridial neurotoxin. Recovering the expressed engineered clostridial neurotoxin may comprise lysing the host cell to provide a host cell homogenate containing the single-chain (engineered) clostridial neurotoxin protein, and/or isolating the single-chain (engineered) clostridial neurotoxin protein. Said method may further comprise a step of introducing the polynucleotide or expression vector described herein into the host cell. Suitable host cells include bacterial cell lines used for the recombinant production of clostridial neurotoxins, particularly Escherichia coli cells. The present invention provides a method for proteolytically processing an (engineered) clostridial neurotoxin of the present invention into a corresponding di-chain clostridial neurotoxin, the method comprising contacting the (engineered) clostridial neurotoxin with one or more exogenous protease thereby producing a di-chain clostridial neurotoxin (e.g. wherein the light chain and heavy chain are joined together by a disulphide bond). The present invention therefore provides a di-chain clostridial neurotoxin obtainable by a method of the invention. The term “obtainable” as used herein also encompasses the term “obtained”. Preferably the term “obtainable” means obtained. Activation of an Engineered Clostridial Neurotoxin The invention provides a method for proteolytically processing an engineered clostridial neurotoxin of the invention into a corresponding di-chain clostridial neurotoxin, the method comprising contacting the engineered clostridial neurotoxin with one or more exogenous protease, thereby producing a di-chain clostridial neurotoxin. Said contacting may be in vitro, ex vivo, or in vivo, preferably in vitro. The therapeutic methods and uses of the invention may comprise the in vivo activation of an engineered clostridial neurotoxin of the invention by cleavage at the one or more exogenous protease activation site by one or more exogenous protease expression within target cells. Thus, a method of the invention may further comprise contacting an engineered clostridial neurotoxin with one or more exogenous protease thereby producing a corresponding di-chain engineered clostridial neurotoxin. Preferably said contacting occurs in vitro. The invention also provides a method for proteolytically processing a single-chain clostridial neurotoxin into a corresponding di-chain clostridial neurotoxin, the method comprising: (a) providing a single-chain clostridial neurotoxin; and (b) contacting the single- chain clostridial neurotoxin with one or more exogenous protease; wherein the single-chain clostridial neurotoxin has an activation loop comprising or consisting of one or more exogenous protease consensus sequence (e.g. any one or more of SEQ ID NOs: 169, 170, 172 or 173) or cleavage site as described herein (e.g. any one or more of SEQ ID NOs: 15- 22, 24-30, 32-42, 44-46 and/or 50-52, particularly any one of SEQ ID NOs: 15-22, 24-30 and/or 32-42, preferably any one of SEQ ID NOs: 15, 17, 16, 26, 25, 27, 24, 33 and/or 32, with SEQ ID NOs: 15, 17, 16, 26, 25 and/or 33 being particularly preferred ); and wherein one or more exogenous protease hydrolyses a peptide bond of the activation loop thereby producing a di- chain clostridial neurotoxin. Preferably said contacting occurs in vitro. The present invention encompasses contacting a single-chain clostridial neurotoxin (e.g. an engineered clostridial neurotoxin of the invention) with one or more exogenous protease, wherein one or more exogenous protease is capable of hydrolysing a peptide bond in an activation loop of the single-chain clostridial neurotoxin thereby producing a di-chain clostridial neurotoxin. Preferably said contacting occurs in vitro. The contacting can occur under any suitable conditions that result in the production of greater than 30%, 40%, 50% or 60% (preferably greater than 70%) of single-chain clostridial neurotoxin being proteolytically processed into the corresponding di-chain clostridial neurotoxin without, or without substantial, hydrolysis of a peptide bond outside of the activation loop of said clostridial neurotoxin. “Without substantial hydrolysis” may mean less than 5%, 4%, 3%, 2% or 1% of the clostridial neurotoxins contacted contain a peptide bond outside of the activation loop that has been hydrolysed by one or more exogenous protease in a method of the invention. The skilled person can select appropriate reaction times, temperatures, buffers, and molar ratios of protease to single-chain clostridial neurotoxin to achieve the above. Optimisation of such conditions can be determined empirically using routine techniques, such as SDS-PAGE (e.g. stained with Coomassie or a dye of similar sensitivity) visual analysis of the reaction products following said contacting or spectrometric techniques (e.g. mass spectrometry). When assessed by SDS-PAGE (e.g. stained with Coomassie or a dye of similar sensitivity), a method of the invention preferably results in the production of a clostridial neurotoxin L-chain and H-chain only. The proteolytic processing by one or more exogenous protease in a method of the invention typically results in the production of less than 5 degradation products of a clostridial neurotoxin L-chain or H-chain, more preferably less than 4, 3, 2 or 1 degradation products. Preferably, the L-chain and H-chain produced by a method of the invention are full-length L- chain and H-chain. Typically, processing by each of the one or more exogenous protease in a method of the invention hydrolyses 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer or a single peptide bond within the engineered clostridial neurotoxin, preferably hydrolysis of one or two peptide bonds. Preferably processing by each of the one or more exogenous protease in a method of the invention hydrolyses 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer or a single peptide bond within the activation loop of the engineered clostridial neurotoxin, preferably hydrolysis of one or two peptide bonds. Where two or more exogenous protease cleavage sites are present within an engineered clostridial neurotoxin of the invention, the total number of peptide bonds that may be hydrolysed by the two or more exogenous proteases is typically 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, 2 or fewer. Preferably a single peptide bond is hydrolysed by each of the two or more exogenous proteases. Exemplary exogenous protease cleavage sites are described herein, with the position of the peptide bond that is hydrolysed indicated. For in vitro activation of engineered clostridial neurotoxins by one or more exogenous protease of the invention, any appropriate conditions for activation may be used. It is within the routine practice of one of ordinary skill in the art to determine suitable conditions. By way of non-limiting example, between about 0.5µg to about 10µg of thrombin may be used per 1mg of engineered clostridial neurotoxin, with activation carried out at room temperature (about 20°C) and a pH of about 7.2 for 1 hour. By way of a further non-limiting example, between about 0.5µg to about 10µg of u-PA may be used per 1mg of engineered clostridial neurotoxin, with activation carried out at room temperature (about 20°C) and a pH of about 7.2 for 1 hour. By way of a yet further non-limiting example, between about 0.5µg to about 100µg of t-PA may be used per 1mg of engineered clostridial neurotoxin, with activation carried out at room temperature (about 20°C) and a pH of about 7.2 for 1 hour. The step of contacting a clostridial neurotoxin with one or more exogenous protease according to the invention may occur within a patient treated with the clostridial neurotoxin. In other words, contacting a clostridial neurotoxin with one or more exogenous protease according to the invention may involve one or more exogenous protease endogenously present within the patient. Accordingly, contacting a clostridial neurotoxin with one or more exogenous protease according to the invention may occur in vivo following administration of the clostridial neurotoxin to an individual. When the contacting step occurs in vivo, it typically involves one or more exogenous protease endogenously present within the patient treated according to the invention. Typically the step of contacting a clostridial neurotoxin with one or more exogenous protease according to the invention occurs in vitro, e.g. during manufacture of the engineered clostridial neurotoxin. The invention also provides a di-chain clostridial neurotoxin that is obtainable by a method of the invention. As activation to the di-chain form occurs by cleavage at one or more exogenous protease cleavage site as described herein, the resulting C- and N-terminal cleaved ends of the di-chain clostridial neurotoxin will differ in sequence compared with the corresponding (pre-engineering) clostridial neurotoxin. By way of non-limiting example: (a) the C-terminal end of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence LVPR, preferably ALVPR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence GSK or GSY; (b) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence SLVPR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence GSY; (c) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence LTPR, preferably ALTPR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence GVR, preferably GVRL; (d) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence PGR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence VVG; (e) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence DKR, preferably AIDKR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence VLY; (f) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence DKR, preferably AIDK, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence RVLY; (g) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence SGR, preferably PGSGR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence SA, preferably SAY, SAG or SAS; (h) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence SGR, preferably PGSGR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence TL, preferably TLD or TLDC; (i) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence FGR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence SA, preferably SAG; or (j) the C-terminus of the cleaved engineered clostridial neurotoxin light chain may end with the amino acid sequence VVPR, and the N-terminus of the cleaved engineered clostridial neurotoxin heavy chain may begin with the amino acid sequence VELVA. In contrast, conventional trypsin cleavage of the (pre-engineering) BoNT/A will result in a di-chain having a LC with a C-terminus ending with the sequence TSK, and a HC with an N-terminus beginning ALNDLC. These di-chain clostridial neurotoxins may be used in therapy as described herein. All disclosure herein in relation to therapeutic indications and formulations in the context of engineered or single-chain clostridial neurotoxins of the invention applies equally and without reservation to di-chain clostridial neurotoxin that is obtainable by a method of the invention unless otherwise stated. Therapy and Formulations A clostridial neurotoxin of the present invention suitably finds utility in medicine and/or in cosmetics. In use, as the engineered clostridial neurotoxin of the invention may be cleaved in vivo by one or more exogenous protease as described herein, the clostridial neurotoxin may be in a single-chain form for administration. Preferably, the engineered clostridial neurotoxin of the invention is for administration in di-chain form (e.g. having been obtained by a method of the invention). The (engineered) clostridial neurotoxins of the invention may be used to prevent or treat certain medical or cosmetic diseases and conditions. Thus, in a further aspect, the present invention provides a di-chain (engineered) clostridial neurotoxin as described above, for use in medicine. In addition, as described herein, the invention relates to single-chain clostridial neurotoxins for use to prevent or treat certain medical or cosmetic diseases and conditions, wherein the single-chain clostridial neurotoxin is administered to a subject. In addition, as described herein, the invention relates to a di-chain clostridial neurotoxin that is obtainable by a method of the invention for use to prevent or treat certain medical or cosmetic diseases and conditions, wherein the di-chain clostridial neurotoxin that is obtainable by a method of the invention is administered to a subject. Thus, in a further aspect, the present invention provides an (engineered) clostridial neurotoxin as described above, for use in medicine. Accordingly, the present invention provides a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) as described above, for use in the prevention or treatment of a disease or condition selected from: a condition associated with unwanted immune secretion, strabismus, blepharospasm, squint, dystonia (e.g. spasmodic dystonia, oromandibular dystonia, focal dystonia, tardive dystonia, laryngeal dystonia, limb dystonia, cervical dystonia), torticollis (e.g. spasmodic torticollis), beauty therapy (cosmetic) applications benefiting from cell/muscle incapacitation (via SNARE down-regulation or inactivation), neuromuscular disorder or condition of ocular motility (e.g. concomitant strabismus, vertical strabismus, lateral rectus palsy, nystagmus, dysthyroid myopathy), writer's cramp, bruxism, Wilson's disease, tremor, tics, segmental myoclonus, spasms, spasticity due to chronic multiple sclerosis, spasticity resulting in abnormal bladder control, animus, back spasm, charley horse, levator pelvic syndrome, spina bifida, tardive dyskinesia, Parkinson's disease, stuttering, hemifacial spasm, eyelid disorder, cerebral palsy, focal spasticity, spasmodic colitis, neurogenic bladder, anismus, limb spasticity, tics, tremors, bruxism, anal fissure, achalasia, dysphagia, lacrimation, hyperhydrosis, excessive salivation, excessive gastrointestinal secretions, muscle pain (e.g. pain from muscle spasms), headache pain (e.g. tension headache or migraine), phantom pain (e.g. phantom limb pain), brow furrows, skin wrinkles, cancer, uterine disorders, uro-genital disorders, urogenital-neurological disorders, bladder pain syndrome, interstitial cystitis, chronic neurogenic inflammation, and a smooth muscle disorder. In some instances, the condition may be selected from phantom pain (e.g. phantom limb pain) and bladder pain syndrome. Similarly, the invention also relates to single-chain clostridial neurotoxins and di-chain clostridial neurotoxins that are obtainable by a method of the invention for use in the treatment or prevention of the above-mentioned diseases or conditions. Preferably, a composition of the invention may be used in the prevention or treatment of a disease or condition selected from: limb spasticity (upper or lower); cervical dystonia; headache disorders (preferably migraine); blepharospasm; hemifacial spasm; and lower urinary tract disorders (e.g. bladder pain syndrome (preferably interstitial cystitis); overactive bladder; and detrusor overactivity (e.g. neurogenic detrusor overactivity. Where a clostridial neurotoxin of the invention (e.g. an engineered clostridial neurotoxin) comprises a BoNT/X sequence (or portion thereof) said clostridial neurotoxin may be able to target other types of secretory cells other than neurons, due to its ability to cleave VAMP4, VAMP5 and/or Ykt6. In some embodiments, the secretory cell targeted is a secretory immune cell. A “secretory immune cell” as used herein, refers to immune cells that secrets cytokines, chemokines, or antibodies. Such secretory immune cells may be innate immune cells including, without limitation, natural killer cells, mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. Secretory immune cells that secret antibodies (e.g. white blood cells) may also be targeted by the clostridial neurotoxins of the present disclosure. Non-limiting examples of antibody secreting cells include, without limitation, plasma B cells, plasmocytes, plasmacytes, and effector B cells. In some embodiments, the clostridial neurotoxin may modulate an immune response. Thus, further contemplated herein are therapeutic use of a clostridial neurotoxin of the invention to treat a condition associated with unwanted secretion, preferably unwanted immune secretion. Conditions associated with unwanted immune secretion include, without limitation: inflammation, psoriasis, allergy, haemophagocytic lymphohistiocytosis, and alcoholic pancreatic disease. The invention also provides the use of a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin or a di-chain clostridial neurotoxin that is obtainable by a method of the invention) as described above, in the manufacture of a medicament for use in a method for preventing or treating a disease or disorder as described herein. The invention also provides a method of treating a disease or disorder as described herein, said method comprising administering a therapeutically effective amount of an clostridial neurotoxin (e.g. an engineered clostridial neurotoxin or a di-chain clostridial neurotoxin that is obtainable by a method of the invention) as described above to a subject in need thereof. The invention also provides the non-therapeutic use of a composition as described herein for treating an aesthetic or cosmetic condition. For cosmetic or aesthetic use, the individual to be treated is preferably not suffering from a disease or disorder, such as those associated with unwanted neuronal activity and described above. More preferably, said individual is a healthy individual, i.e. an individual which is not suffering from any disease. Preferably, a composition of the invention may be used in the prevention or treatment of upper facial lines - glabellar lines, lateral canthal lines and/or intrathecal lines. The invention provides a pharmaceutical composition comprising an (engineered) clostridial neurotoxin or a di-chain clostridial neurotoxin of the invention and a pharmaceutically acceptable carrier, excipient, adjuvant, propellant and/or salt. Preferably the (engineered) clostridial neurotoxin is in single-chain form (e.g. engineered to comprise a one or more exogenous protease cleavage site). A pharmaceutical composition of the invention may be a liquid composition (or formulation) or a solid composition (or formulation). The invention also provides a cosmetic composition comprising an (engineered) clostridial neurotoxin of the invention or a di-chain clostridial neurotoxins of the invention and a cosmetically acceptable carrier, excipient, diluent, adjuvant, propellant and/or salt. The invention also provides the use of a cosmetic composition comprising a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin or a di-chain clostridial neurotoxin that is obtainable by a method of the invention) for preventing or alleviating a cosmetic indication for which the application of a botulinum neurotoxin is indicated. The invention also provides the use of a cosmetic composition comprising a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin or a di-chain clostridial neurotoxin that is obtainable by a method of the invention) for preventing or alleviating a cosmetic indication for which the application of a botulinum neurotoxin is indicated. Preferably the (engineered) clostridial neurotoxin is in di-chain form (e.g. engineered to comprise one or more exogenous protease cleavage site and cleavage by one or more exogenous protease during manufacturing). A cosmetic composition of the invention may be a liquid composition (or formulation) or a solid composition (or formulation). The clostridial neurotoxins of the present invention (e.g. an engineered clostridial neurotoxin) may be formulated for oral, parenteral, continuous infusion, inhalation or topical application. Compositions suitable for injection may be in the form of solutions, suspensions or emulsions, or dry powders which are dissolved or suspended in a suitable vehicle prior to use. A liquid composition of the invention may be (i) a pre-lyophilisation solution, (ii) a post- reconstitution solution, or (iii) a solution which is not intended for lyophilisation and/or which has not undergone post-lyophilisation reconstitution. Liquid compositions of class (iii) may also be referred to as a “ready-to-use” compositions or “ready-to-use” solutions, as they are manufactured and formulated as a liquid and sold for use in liquid form. All disclosure herein in relation to liquid formulations applies to any liquid formulation, including pre-lyophilisation solutions, post-reconstitution solutions and ready-to-use compositions, unless expressly stated to the contrary. A liquid composition may be packaged based on the amount (particularly the absolute weight) of the chimeric clostridial neurotoxin of the invention, as described herein. The liquid composition may be packaged to allow for up to 15 injections to be administered from a single container. A solid composition may be packaged based on the amount (particularly the absolute weight) of the engineered clostridial neurotoxin of the invention, as described herein In the case of a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) that is to be delivered locally, the clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) may be formulated as a cream (e.g. for topical application), or for sub-dermal injection. Local delivery means may include an aerosol, or other spray (e.g. a nebuliser). In this regard, an aerosol formulation of a clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) enables delivery to the lungs and/or other nasal and/or bronchial or airway passages. Clostridial neurotoxins of the invention (e.g. an engineered clostridial neurotoxin) may be administered to a patient by intrathecal or epidural injection in the spinal column at the level of the spinal segment involved in the innervation of an affected organ. A preferred route of administration is via laproscopic and/ or localised, particularly intramuscular, injection. The dosage ranges for administration of the compositions of the present invention are those to produce the desired therapeutic effect. A therapeutically effective dose refers to an amount of the chimeric neurotoxin, to be used in a composition of the present invention which prevents, ameliorates or treats the symptoms accompanying a disease or condition referred herein. Therapeutic efficacy and toxicity of the compound are typically determined in the art by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. In general terms, it will be appreciated that the dosage range required for a given pharmaceutical depends on the precise nature of the composition, the route of administration, the nature of the formulation, the age of the patient, the nature, extent or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician. In relation to the engineered neurotoxin compositions of the invention, suitable single unit doses (also referred to as unit doses), i.e. the dose administered per injection site are described in the art, such as in WO2021/186160, WO2021/186167, WO2023/047127, WO2023/089343 and WO2023/041934, each of which is herein incorporated by reference in its entirety. By way of non-limiting example, a single unit dose is 15,000 pg of engineered neurotoxin, 25,000 pg of engineered neurotoxin or 36,000 pg of engineered neurotoxin. A treatment may comprise injections at multiple injection sites (typically no more than 20, preferably no more than 15 injection sites), with a single unit dose injected at each injection site. Fluid dosage forms are typically prepared utilising the clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) and a pyrogen-free sterile vehicle. The clostridial neurotoxin (e.g. an engineered clostridial neurotoxin), depending on the vehicle and concentration used, can be either dissolved or suspended in the vehicle. In preparing solutions the clostridial neurotoxin (e.g. an engineered clostridial neurotoxin) can be dissolved in the vehicle, the solution being made isotonic if necessary by addition of sodium chloride and sterilised by filtration through a sterile filter using aseptic techniques before filling into suitable sterile vials or ampoules and sealing. Alternatively, if solution stability is adequate, the solution in its sealed containers may be sterilised by autoclaving. Advantageously additives such as buffering, solubilising, stabilising, preservative or bactericidal, suspending or emulsifying agents and or local anaesthetic agents may be dissolved in the vehicle. Dry powders, which are dissolved or suspended in a suitable vehicle prior to use, may be prepared by filling pre-sterilised ingredients into a sterile container using aseptic technique in a sterile area. Alternatively the ingredients may be dissolved into suitable containers using aseptic technique in a sterile area. The product is then freeze dried and the containers are sealed aseptically. Parenteral suspensions, suitable for intramuscular, subcutaneous or intradermal injection, are prepared in substantially the same manner, except that the sterile components are suspended in the sterile vehicle, instead of being dissolved and sterilisation cannot be accomplished by filtration. The components may be isolated in a sterile state or alternatively it may be sterilised after isolation, e.g. by gamma irradiation. Advantageously, a suspending agent for example polyvinylpyrrolidone is included in the composition(s) to facilitate uniform distribution of the components. Administration in accordance with the present invention may take advantage of a variety of delivery technologies including microparticle encapsulation, viral delivery systems or high-pressure aerosol impingement. Disclosure related to the various methods of the invention are intended to be applied equally to other methods, the clostridial neurotoxins, e.g. engineered clostridial neurotoxins (whether in single-chain or di-chain forms), uses or pharmaceutical compositions, as well as medical uses thereof and vice versa. SEQUENCE HOMOLOGY Any of a variety of sequence alignment methods can be used to determine percent identity, including, without limitation, global methods, local methods and hybrid methods, such as, e.g., segment approach methods. Protocols to determine percent identity are routine procedures within the scope of one skilled in the art. Global methods align sequences from the beginning to the end of the molecule and determine the best alignment by adding up scores of individual residue pairs and by imposing gap penalties. Non-limiting methods include, e.g., CLUSTAL W, see, e.g., Julie D. Thompson et al., CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting, Position- Specific Gap Penalties and Weight Matrix Choice, 22(22) Nucleic Acids Research 4673-4680 (1994); and iterative refinement, see, e.g., Osamu Gotoh, Significant Improvement in Accuracy of Multiple Protein. Sequence Alignments by Iterative Refinement as Assessed by Reference to Structural Alignments, 264(4) J. MoI. Biol.823-838 (1996). Local methods align sequences by identifying one or more conserved motifs shared by all of the input sequences. Non-limiting methods include, e.g., Match-box, see, e.g., Eric Depiereux and Ernest Feytmans, Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences, 8(5) CABIOS 501 -509 (1992); Gibbs sampling, see, e.g., C. E. Lawrence et al., Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment, 262(5131 ) Science 208-214 (1993); Align-M, see, e.g., Ivo Van WaIIe et al., Align-M - A New Algorithm for Multiple Alignment of Highly Divergent Sequences, 20(9) Bioinformatics:1428-1435 (2004). Thus, percent sequence identity is determined by conventional methods. See, for example, Altschul et al., Bull. Math. Bio.48: 603-16, 1986 and Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-19, 1992. Briefly, two amino acid sequences are aligned to optimize the alignment scores using a gap opening penalty of 10, a gap extension penalty of 1, and the "blosum 62" scoring matrix of Henikoff and Henikoff (ibid.) as shown below (amino acids are indicated by the standard one-letter codes). The "percent sequence identity" between two or more nucleic acid or amino acid sequences is a function of the number of identical positions shared by the sequences. Thus, % identity may be calculated as the number of identical nucleotides / amino acids divided by the total number of nucleotides / amino acids, multiplied by 100. Calculations of % sequence identity may also take into account the number of gaps, and the length of each gap that needs to be introduced to optimize alignment of two or more sequences. Sequence comparisons and the determination of percent identity between two or more sequences can be carried out using specific mathematical algorithms, such as BLAST, which will be familiar to a skilled person. ALIGNMENT SCORES FOR DETERMINING SEQUENCE IDENTITY A R N D C Q E G H I L K M F P S T W Y V A 4 R -1 5 N -2 0 6 D -2 -2 1 6 C 0 -3 -3 -3 9 Q -1 1 0 0 -3 5 E -1 0 0 2 -4 2 5 G 0 -2 0 -1 -3 -2 -2 6 H -2 0 1 -1 -3 0 0 -2 8 I -1 -3 -3 -3 -1 -3 -3 -4 -3 4 L -1 -2 -3 -4 -1 -2 -3 -4 -3 2 4 K -1 2 0 -1 -3 1 1 -2 -1 -3 -2 5 M -1 -1 -2 -3 -1 0 -2 -3 -2 1 2 -1 5 F -2 -3 -3 -3 -2 -3 -3 -3 -1 0 0 -3 0 6 P -1 -2 -2 -1 -3 -1 -1 -2 -2 -3 -3 -1 -2 -4 7 S 1 -1 1 0 -1 0 0 0 -1 -2 -2 0 -1 -2 -1 4 T 0 -1 0 -1 -1 -1 -1 -2 -2 -1 -1 -1 -1 -2 -1 1 5 W -3 -3 -4 -4 -2 -2 -3 -2 -2 -3 -2 -3 -1 1 -4 -3 -211 Y -2 -2 -2 -3 -2 -1 -2 -3 2 -1 -1 -2 -1 3 -3 -2 -2 2 7 V 0 -3 -3 -3 -1 -2 -2 -3 -3 3 1 -2 1 -1 -2 -2 0 -3 -1 4 The percent identity is then calculated as: Total number of identical matches __________________________________________ x 100 [length of the longer sequence plus the number of gaps introduced into the longer sequence in order to align the two sequences] Substantially homologous polypeptides are characterized as having one or more amino acid substitutions, deletions or additions. These changes are preferably of a minor nature, that is conservative amino acid substitutions (see below) and other substitutions that do not significantly affect the folding or activity of the polypeptide; small deletions, typically of one to about 30 amino acids; and small amino- or carboxyl-terminal extensions, such as an amino-terminal methionine residue, a small linker peptide of up to about 20-25 residues, or an affinity tag. CONSERVATIVE AMINO ACID SUBSTITUTIONS Basic: arginine lysine histidine Acidic: glutamic acid aspartic acid Polar: glutamine asparagine Hydrophobic: leucine isoleucine valine Aromatic: phenylalanine tryptophan tyrosine Small: glycine alanine serine threonine methionine In addition to the 20 standard amino acids, non-standard amino acids (such as 4- hydroxyproline, 6-N-methyl lysine, 2-aminoisobutyric acid, isovaline and α -methyl serine) may be substituted for amino acid residues of the polypeptides of the present invention. A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, and unnatural amino acids may be substituted for polypeptide amino acid residues. The polypeptides of the present invention can also comprise non-naturally occurring amino acid residues. Non-naturally occurring amino acids include, without limitation, trans-3-methylproline, 2,4-methano-proline, cis-4-hydroxyproline, trans-4-hydroxy-proline, N-methylglycine, allo- threonine, methyl-threonine, hydroxy-ethylcysteine, hydroxyethylhomo-cysteine, nitro- glutamine, homoglutamine, pipecolic acid, tert-leucine, norvaline, 2-azaphenylalanine, 3- azaphenyl-alanine, 4-azaphenyl-alanine, and 4-fluorophenylalanine. Several methods are known in the art for incorporating non-naturally occurring amino acid residues into proteins. For example, an in vitro system can be employed wherein nonsense mutations are suppressed using chemically aminoacylated suppressor tRNAs. Methods for synthesizing amino acids and aminoacylating tRNA are known in the art. Transcription and translation of plasmids containing nonsense mutations is carried out in a cell free system comprising an E. coli S30 extract and commercially available enzymes and other reagents. Proteins are purified by chromatography. See, for example, Robertson et al., J. Am. Chem. Soc.113:2722, 1991; Ellman et al., Methods Enzymol.202:301, 1991; Chung et al., Science 259:806-9, 1993; and Chung et al., Proc. Natl. Acad. Sci. USA 90:10145-9, 1993). In a second method, translation is carried out in Xenopus oocytes by microinjection of mutated mRNA and chemically aminoacylated suppressor tRNAs (Turcatti et al., J. Biol. Chem.271:19991-8, 1996). Within a third method, E. coli cells are cultured in the absence of a natural amino acid that is to be replaced (e.g., phenylalanine) and in the presence of the desired non-naturally occurring amino acid(s) (e.g., 2-azaphenylalanine, 3-azaphenylalanine, 4-azaphenylalanine, or 4- fluorophenylalanine). The non-naturally occurring amino acid is incorporated into the polypeptide in place of its natural counterpart. See, Koide et al., Biochem.33:7470-6, 1994. Naturally occurring amino acid residues can be converted to non-naturally occurring species by in vitro chemical modification. Chemical modification can be combined with site-directed mutagenesis to further expand the range of substitutions (Wynn and Richards, Protein Sci. 2:395-403, 1993). A limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, non-naturally occurring amino acids, and unnatural amino acids may be substituted for amino acid residues of polypeptides of the present invention. Essential amino acids in the polypeptides of the present invention can be identified according to procedures known in the art, such as site-directed mutagenesis or alanine- scanning mutagenesis (Cunningham and Wells, Science 244: 1081-5, 1989). Sites of biological interaction can also be determined by physical analysis of structure, as determined by such techniques as nuclear magnetic resonance, crystallography, electron diffraction or photoaffinity labeling, in conjunction with mutation of putative contact site amino acids. See, for example, de Vos et al., Science 255:306-12, 1992; Smith et al., J. Mol. Biol.224:899-904, 1992; Wlodaver et al., FEBS Lett.309:59-64, 1992. The identities of essential amino acids can also be inferred from analysis of homologies with related components (e.g. the translocation or protease components) of the polypeptides of the present invention. Multiple amino acid substitutions can be made and tested using known methods of mutagenesis and screening, such as those disclosed by Reidhaar-Olson and Sauer (Science 241:53-7, 1988) or Bowie and Sauer (Proc. Natl. Acad. Sci. USA 86:2152-6, 1989). Briefly, these authors disclose methods for simultaneously randomizing two or more positions in a polypeptide, selecting for functional polypeptide, and then sequencing the mutagenized polypeptides to determine the spectrum of allowable substitutions at each position. Other methods that can be used include phage display (e.g., Lowman et al., Biochem.30:10832-7, 1991; Ladner et al., U.S. Patent No.5,223,409; Huse, WIPO Publication WO 92/06204) and region-directed mutagenesis (Derbyshire et al., Gene 46:145, 1986; Ner et al., DNA 7:127, 1988). SEQUENCE INFORMATION Where an initial Met amino acid residue or a corresponding initial codon is indicated in any of the following SEQ ID NOs, said residue/codon is optional. SEQ ID NO: 1 C1 activation loop consensus C-(X) _a -I-D/E-G-R-(Y) _b -C wherein a = 1-10 and b = 4-15 SEQ ID NO: 2 C1 activation loop CHKAIDGRSLYNKTLDC SEQ ID NO: 3 C1 activation loop CHKAIEGRSLYNKTLDC SEQ ID NO: 4 N-terminal residues of modified C1 activation loop CHKA SEQ ID NO: 5 N-terminal residues of modified C1 activation loop CHKAI SEQ ID NO: 6 N-terminal residues of modified C1 activation loop CHKAID SEQ ID NO: 7 Residues missing from modified C1 activation loop IDGR SEQ ID NO: 8 Residues missing from modified C1 activation loop IEGR SEQ ID NO: 9 Residues missing from modified C1 activation loop CHKAIDGR SEQ ID NO: 10 Residues missing from modified C1 activation loop CHKAIEGR SEQ ID NO: 11 C-terminal residues of modified C1 activation loop TLDC SEQ ID NO: 12 C-terminal residues of modified C1 activation loop KTLDC SEQ ID NO: 13 C-terminal residues of modified C1 activation loop YNKTLDC SEQ ID NO: 14 C-terminal residues of modified C1 activation loop LYNKTLDC SEQ ID NO: 15 thrombin cleavage site LTPRGVRL SEQ ID NO: 16 thrombin cleavage site LVPRGS SEQ ID NO: 17 thrombin cleavage site ENKSLVPRGS SEQ ID NO: 18 thrombin cleavage site consensus X1-X2-X3-R-X4-X5-X6-X7 where: X ₃ is P, A, L or G X4 is S, A or G SEQ ID NO: 19 thrombin cleavage site consensus X ₁ -X ₂ -X ₃ -X ₄ -X ₅ -X ₆ -X ₇ -X ₈ where: X ₃ is P, A, L or G X4 is R or K X ₅ is S, A or G SEQ ID NO: 20 thrombin cleavage site consensus X1-X2- X3-X4-X5-X6-X7-X8 where: X4 is R or K SEQ ID NO: 21 thrombin cleavage site consensus X1-X2-P-R-X3-X4-X5-X6 where: X3 is S, A or G SEQ ID NO: 22 thrombin cleavage site consensus X ₁ -X ₂ - P-K-X ₃ -X ₄ -X ₅ -X ₆ where: X3 is S, A or G SEQ ID NO: 23 thrombin MAHVRGLQLPGCLALAALCSLVHSQHVFLAPQQARSLLQRVRRANTFLEEVRKGNLEREC VEETCSYE EAFEALESSTATDVFWAKYTACETARTPRDKLAACLEGNCAEGLGTNYRGHVNITRSGIE CQLWRSRY PHKPEINSTTHPGADLQENFCRNPDSSTTGPWCYTTDPTVRRQECSIPVCGQDQVTVAMT PRSEGSSV NLSPPLEQCVPDRGQQYQGRLAVTTHGLPCLAWASAQAKALSKHQDFNSAVQLVENFCRN PDGDEEGV WCYVAGKPGDFGYCDLNYCEEAVEEETGDGLDEDSDRAIEGRTATSEYQTFFNPRTFGSG EADCGLRP LFEKKSLEDKTERELLESYIDGRIVEGSDAEIGMSPWQVMLFRKSPQELLCGASLISDRW VLTAAHCL LYPPWDKNFTENDLLVRIGKHSRTRYERNIEKISMLEKIYIHPRYNWRENLDRDIALMKL KKPVAFSD YIHPVCLPDRETAASLLQAGYKGRVTGWGNLKETWTANVGKGQPSVLQVVNLPIVERPVC KDSTRIRI TDNMFCAGYKPDEGKRGDACEGDSGGPFVMKSPFNNRWYQMGIVSWGEGCDRDGKYGFYT HVFRLKKW IQKVIDQFGE SEQ ID NO: 24 urokinase (u-PA) cleavage site KRV SEQ ID NO: 25 urokinase (u-PA) cleavage site SGRSA SEQ ID NO: 26 urokinase (u-PA) cleavage site PGSGRSAG SEQ ID NO: 27 urokinase (u-PA) cleavage site PGSGRSASGTTGTG SEQ ID NO: 28 u-PA cleavage site consensus X ₁ -S-X ₂ -X ₃ -G-X ₄ -X ₅ -X ₆ where: X2 is G or S X ₃ is R or K X4 is L, R or V X ₆ is N or G SEQ ID NO: 29 u-PA cleavage site consensus X1-X2-X3-R-V-X4-X5-X6 SEQ ID NO: 30 u-PA cleavage site consensus X1-S-G-R-G- X1-X2-X3 where: X1 is L, R or V X ₃ is N or G SEQ ID NO: 31 u-PA MRVWLASLFLCALVANSEGGSELEASDESNCGCQNGGVCVSYKYFSSIRRCSCPKKFKGE HCEIDTSK TCYHGNGQSYRGKANTDTKGRPCLAWNSPAVLQQTYNAHRSDALSLGLGKHNYCRNPDNQ RRPWCYVQ IGLKQFVQECMVQDCSLSKKPSSTVDQQGFQCGQKALRPRFKIVGGEFTVVENQPWFAAI YLKNKGGS PPSFKCGGSLISPCWVASATHCFVNQPKKEEYVVYLGQSKRNSYNPGEMKFEVEQLILHE DFSDETLA FHNDIALLKIRTSTGQCAQPSRTIQTICLPPRFGDAPFGSDCEITGFGQESATDYFYPKD LKMSVVKI ISHEQCKQPHYYGSEINYKMLCAADPEWKTDSCSGDSGGPLICNIDGRPTLSGIVSWGSG CAEKNKPG VYTRVSYFLNWIQSHIGEENGLAF SEQ ID NO: 32 tissue plasminogen activator (t-PA) cleavage site VVPRVELVA SEQ ID NO: 33 tissue plasminogen activator (t-PA) cleavage site PPFGRSAG SEQ ID NO: 34 t-PA cleavage site consensus X ₁ -X ₂ -X ₃ -R-X ₄ -X ₅ where: X ₂ is F or Y X ₃ is S, G or A SEQ ID NO: 35 t-PA cleavage site consensus G-P-X1-X2-X3-G-G-X4 where: X2 is K or R SEQ ID NO: 36 t-PA cleavage site consensus X ₁ -X ₂ -X ₃ -R-V-X ₄ -X ₅ -X ₆ SEQ ID NO: 37 t-PA cleavage site consensus X ₁ -X ₂ -X ₃ -R-X ₄ -X ₅ -X ₆ -X ₇ where: X ₂ is F or Y X3 is S, G or A SEQ ID NO: 38 t-PA cleavage site consensus S-X ₁ -X ₂ -R-X ₃ -X ₄ -X ₅ -X ₆ where: X ₁ is F or Y X2 is S, G or A SEQ ID NO: 39 t-PA cleavage site consensus G-P-X1-X2-X3-G-G-X4 where: X2 is K or R SEQ ID NO: 40 t-PA cleavage site consensus G-P-Y-X ₁ -X ₂ -G-G-X ₂ where: X ₁ is F or Y SEQ ID NO: 41 t-PA cleavage site consensus G-P-X ₁ - X ₂ -K-G-G-X ₃ where: X ₂ is K or R SEQ ID NO: 42 t-PA cleavage site consensus G-P-Y-X1-K-G-G-X2 where: X1 is K or R SEQ ID NO: 43 t-PA MDAMKRGLCCVLLLCGAVFVSPSQEIHARFRRGARSYQVICRDEKTQMIYQQHQSWLRPV LRSNRVEY CWCNSGRAQCHSVPVKSCSEPRCFNGGTCQQALYFSDFVCQCPEGFAGKCCEIDTRATCY EDQGISYR GTWSTAESGAECTNWNSSALAQKPYSGRRPDAIRLGLGNHNYCRNPDRDSKPWCYVFKAG KYSSEFCS TPACSEGNSDCYFGNGSAYRGTHSLTESGASCLPWNSMILIGKVYTAQNPSAQALGLGKH NYCRNPDG DAKPWCHVLKNRRLTWEYCDVPSCSTCGLRQYSQPQFRIKGGLFADIASHPWQAAIFAKH RRSPGERF LCGGILISSCWILSAAHCFQERFPPHHLTVILGRTYRVVPGEEEQKFEVEKYIVHKEFDD DTYDNDIA LLQLKSDSSRCAQESSVVRTVCLPPADLQLPDWTECELSGYGKHEALSPFYSERLKEAHV RLYPSSRC TSQHLLNRTVTDNMLCAGDTRSGGPQANLHDACQGDSGGPLVCLNDGRMTLVGIISWGLG CGQKDVPG VYTKVTNYLDWIRDNMRP SEQ ID NO: 44 FVII/FIX cleavage site GRI SEQ ID NO: 45 FIX cleavage site consensus X ₁ - X ₂ -G-R-X ₃ -X ₄ -X ₅ -X ₆ SEQ ID NO: 46 FVII/FIX cleavage site consensus X ₁ - X ₂ - X ₃ -R-I-X ₄ -X ₅ -X ₆ SEQ ID NO: 47 FIX MQRVNMIMAESPGLITICLLGYLLSAECTVFLDHENANKILNRPKRYNSGKLEEFVQGNL ERECMEEK CSFEEAREVFENTERTTEFWKQYVDGDQCESNPCLNGGSCKDDINSYECWCPFGFEGKNC ELDVTCNI KNGRCEQFCKNSADNKVVCSCTEGYRLAENQKSCEPAVPFPCGRVSVSQTSKLTRAETVF PDVDYVNS TEAETILDNITQSTQSFNDFTRVVGGEDAKPGQFPWQVVLNGKVDAFCGGSIVNEKWIVT AAHCVETG VKITVVAGEHNIEETEHTEQKRNVIRIIPHHNYNAAINKYNHDIALLELDEPLVLNSYVT PICIADKE YTNIFLKFGSGYVSGWGRVFHKGRSALVLQYLRVPLVDRATCLRSTKFTIYNNMFCAGFH EGGRDSCQ GDSGGPHVTEVEGTSFLTGIISWGEECAMKGKYGIYTKVSRYVNWIKEKTKLT SEQ ID NO: 48 FVII MVSQALRLLCLLLGLQGCLAAGGVAKASGGETRDMPWKPGPHRVFVTQEEAHGVLHRRRR ANAFLEEL RPGSLERECKEEQCSFEEAREIFKDAERTKLFWISYSDGDQCASSPCQNGGSCKDQLQSY ICFCLPAF EGRNCETHKDDQLICVNENGGCEQYCSDHTGTKRSCRCHEGYSLLADGVSCTPTVEYPCG KIPILEKR NASKPQGRIVGGKVCPKGECPWQVLLLVNGAQLCGGTLINTIWVVSAAHCFDKIKNWRNL IAVLGEHD LSEHDGDEQSRRVAQVIIPSTYVPGTTNHDIALLRLHQPVVLTDHVVPLCLPERTFSERT LAFVRFSL VSGWGQLLDRGATALELMVLNVPRLMTQDCLQQSRKVGDSPNITEYMFCAGYSDGSKDSC KGDSGGPH ATHYRGTWYLTGIVSWGQGCATVGHFGVYTRVSQYIEWLQKLMRSEPRPGVLLRAPFP SEQ ID NO: 49 Plasminogen MEHKEVVLLLLLFLKSGQGEPLDDYVNTQGASLFSVTKKQLGAGSIEECAAKCEEDEEFT CRAFQYHS KEQQCVIMAENRKSSIIIRMRDVVLFEKKVYLSECKTGNGKNYRGTMSKTKNGITCQKWS STSPHRPR FSPATHPSEGLEENYCRNPDNDPQGPWCYTTDPEKRYDYCDILECEEECMHCSGENYDGK ISKTMSGL ECQAWDSQSPHAHGYIPSKFPNKNLKKNYCRNPDRELRPWCFTTDPNKRWELCDIPRCTT PPPSSGPT YQCLKGTGENYRGNVAVTVSGHTCQHWSAQTPHTHNRTPENFPCKNLDENYCRNPDGKRA PWCHTTNS QVRWEYCKIPSCDSSPVSTEQLAPTAPPELTPVVQDCYHGDGQSYRGTSSTTTTGKKCQS WSSMTPHR HQKTPENYPNAGLTMNYCRNPDADKGPWCFTTDPSVRWEYCNLKKCSGTEASVVAPPPVV LLPDVETP SEEDCMFGNGKGYRGKRATTVTGTPCQDWAAQEPHRHSIFTPETNPRAGLEKNYCRNPDG DVGGPWCY TTNPRKLYDYCDVPQCAAPSFDCGKPQVEPKKCPGRVVGGCVAHPHSWPWQVSLRTRFGM HFCGGTLI SPEWVLTAAHCLEKSPRPSSYKVILGAHQEVNLEPHVQEIEVSRLFLEPTRKDIALLKLS SPAVITDK VIPACLPSPNYVVADRTECFITGWGETQGTFGAGLLKEAQLPVIENKVCNRYEFLNGRVQ STELCAGH LAGGTDSCQGDSGGPLVCFEKDKYILQGVTSWGLGCARPNKPGVYVRVSRFVTWIEGVMR NN SEQ ID NO: 50 Plasminogen cleavage site PGRVVGG SEQ ID NO: 51 Plasminogen cleavage site consensus X ₁ - X ₂ - X ₃ -K-X ₄ -X ₅ -X ₆ -X ₇ SEQ ID NO: 52 Plasminogen cleavage site consensus X1- X2- X3-R-X4-X5-X6-X7 SEQ ID NO: 53 modified C-loop with minimal uPA/tPA cleavage site CHKAIDKRVLYNKTLDC SEQ ID NO: 54 modified C-loop with minimal thrombin cleavage site CHKALVPRGSYNKTLDC SEQ ID NO: 55 modified C-loop with minimal FIX/FVII cleavage site CHKAIDGRILYNKTLDC SEQ ID NO: 56 modified C-loop with full thrombin cleavage site CHKAENKSLVPRGSYNKTLDC SEQ ID NO: 57 modified C-loop with alternative thrombin cleavage site CHKALTPRGVRLKTLDC SEQ ID NO: 58 modified C-loop with native plasminogen cleavage site CPGRVVGGC SEQ ID NO: 59 modified C-loop with native plasminogen cleavage site with spacers CGGGGSPGRVVGGGGSC SEQ ID NO: 60 optimal u-PA cleavage site in plasminogen loop CSGRSAGGC SEQ ID NO: 61 optimal u-PA cleavage site with spacers CGGGGSGRSAGGGGSC SEQ ID NO: 62 modified C-loop with alternative t-PA cleavage site CHKAVVPRVELVATLDC SEQ ID NO: 63 modified C-loop with alternative t-PA cleavage site CHKAIPPFGRSAGYNKTLDC SEQ ID NO: 64 modified C-loop with alternative t-PA cleavage site CHKAIPGSGRSAGYNKTLDC SEQ ID NO: 65 modified C-loop with alternative u-PA cleavage site CHKAISGRSAYNKTLDC SEQ ID NO: 66 modified C-loop with alternative t-PA cleavage site CHKAIPGSGRSASGTTGTGYNKTLDC SEQ ID NO: 67 endogenous BoNT/D Activation Loop CLRLTKNSRDDSTC SEQ ID NO: 68 endogenous BoNT/DC Activation Loop CLRLTRNSRDDSTC SEQ ID NO: 69 endogenous BoNT/C1 and CD Activation Loop CHKAIDGRSLYNKTLDC SEQ ID NO: 70 endogenous BoNT/A4 Activation Loop CVRGIITSKTKSLDEGYNKALNELC SEQ ID NO: 71 endogenous BoNT/A5 and A7 Activation Loop CVRGIITSKTKSLDEGYNKALNDLC SEQ ID NO: 72 endogenous BoNT/A1 and A6 Activation Loop CVRGIITSKTKSLDKGYNKALNDLC SEQ ID NO: 73 endogenous BoNT/A3 Activation Loop CVRGIIPFKTKSLDEGYNKALNYLC SEQ ID NO: 74 endogenous BoNT/A2 and A8 Activation Loop CVRGIIPFKTKSLDEGYNKALNDLC SEQ ID NO: 75 endogenous BoNT/H Activation Loop CSNSNTKNSLC SEQ ID NO: 76 endogenous BoNT/E1 to E5, E9 and E12 Activation Loop CKNIVSVKGIRKSIC SEQ ID NO: 77 endogenous BoNT/E11 Activation Loop CTNIFSPKGIRKSIC SEQ ID NO: 78 endogenous BoNT/E7, E8 and E10 Activation Loop CKNIVFSKGITKSIC SEQ ID NO: 79 endogenous BoNT/E6 Activation Loop CKNIVFSKGIRKSIC SEQ ID NO: 80 endogenous BoNT/F7 Activation Loop CKSIVSKKGTKNSLC SEQ ID NO: 81 endogenous BoNT/F5 Activation Loop CLNSSFKKNTKKPLC SEQ ID NO: 82 endogenous BoNT/F1 and F6 Activation Loop CKSVIPRKGTKAPPRLC SEQ ID NO: 83 endogenous BoNT/F4 Activation Loop CKSIIPRKGTKAPPRLC SEQ ID NO: 84 endogenous BoNT/F2 and F3 Activation Loop CKSIIPRKGTKQSPSLC SEQ ID NO: 85 endogenous TeNT Activation Loop CKKIIPPTNIRENLYNRTASLTDLGGELC SEQ ID NO: 86 endogenous BoNT/G Activation Loop CKPVMYKNTGKSEQC SEQ ID NO: 87 endogenous BoNT/B4 Activation Loop CKSVKVPGIC SEQ ID NO: 88 endogenous BoNT/B2, B3, B6 and B8 Activation Loop CKSVRAPGIC SEQ ID NO: 89 endogenous BoNT/B1, B5 and B7 Activation Loop CKSVKAPGIC SEQ ID NO: 90 endogenous BoNT/X Activation Loop CPRNGLLYNAIYRNSKNYLNNIDLEDKKTTSKTNVSYPCSLLNGC SEQ ID NO: 91 (BoNT/A1 - UniProt P10845) MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGG STIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGY GSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPN RVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFT GLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEE ITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNG KKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEA AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG AVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAK VNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKA MININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDK VNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINI GSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNN EYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTIT NNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELN EKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPR GSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQA GVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAK LVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL In some embodiments, valine27 may be substituted with alanine, as shown in SEQ ID NO: 135. The endogenous activation loop is dash-underlined. SEQ ID NO: 92 (BoNT/A2 – GenBank Accession No. X73423.1) MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHDVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAEHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDVASTLNKA KSIIGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVNFFKV INRKTYLNFDKAVFR INIVPDENYTIKDGFNLKGANLSTNFNGQNTEINSRNFTRLKNFTGLFEFYKLLCVRGII PFKTKSLDEGYNKAL NDLCIKVNNWDLFFSPSEDNFTNDLDKVEEITADTNIEAAEENISLDLIQQYYLTFDFDN EPENISIENLSSDII GQLEPMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGDSRIILTNSAEEALLKPNVAYTF FSSKYVKKINKAVEA FMFLNWAEELVYDFTDETNEVTTMDKIADITIIVPYIGPALNIGNMLSKGEFVEAIIFTG VVAMLEFIPEYALPV FGTFAIVSYIANKVLTVQTINNALSKRNEKWDEVYKYTVTNWLAKVNTQIDLIREKMKKA LENQAEATKAIINYQ YNQYTEEEKNNINFNIDDLSSKLNESINSAMININKFLDQCSVSYLMNSMIPYAVKRLKD FDASVRDVLLKYIYD NRGTLVLQVDRLKDEVNNTLSADIPFQLSKYVDNKKLLSTFTEYIKNIVNTSILSIVYKK DDLIDLSRYGAKINI GDRVYYDSIDKNQIKLINLESSTIEVILKNAIVYNSMYENFSTSFWIKIPKYFSKINLNN EYTIINCIENNSGWK VSLNYGEIIWTLQDNKQNIQRVVFKYSQMVNISDYINRWIFVTITNNRLTKSKIYINGRL IDQKPISNLGNIHAS NKIMFKLDGCRDPRRYIMIKYFNLFDKELNEKEIKDLYDSQSNSGILKDFWGNYLQYDKP YYMLNLFDPNKYVDV NNIGIRGYMYLKGPRGSVVTTNIYLNSTLYEGTKFIIKKYASGNEDNIVRNNDRVYINVV VKNKEYRLATNASQA GVEKILSALEIPDVGNLSQVVVMKSKDDQGIRNKCKMNLQDNNGNDIGFIGFHLYDNIAK LVASNWYNRQVGKAS RTFGCSWEFIPVDDGWGESSL The endogenous activation loop is dash-underlined. SEQ ID NO: 93 (BoNT/A3 – GenBank Accession No. DQ185900.1) MPFVNKPFNYRDPGNGVDIAYIKIPNAGQMQPVKAFKIHEGVWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVIKLFDRIYSTGLGRMLLSFIVKGIPFWGGSTIDTELKVIDTNCI NVIEPGGSYRSEELN LVITGPSADIIQFECKSFGHDVFNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GTFATDPAVTLAHEL IHAAHRLYGIAINPNRVLKVKTNAYYEMSGLEVSFEELRTFGGNDTNFIDSLWQKKFSRD AYDNLQNIARILNEA KTIVGTTTPLQYMKNIFIRKYFLSEDASGKISVNKAAFKEFYRVLTRGFTELEFVNPFKV INRKTYLNFDKAVFR INIVPDENYTINEGFNLEGANSNGQNTEINSRNFTRLKNFTGLFEFYKLLCVRGIIPFKT KSLDEGYNKALNYLC IKVNNWDLFFSPSEDNFTNDLDKVEEITADTNIEAAEENISSDLIQQYYLTFDFDNEPEN ISIENLSSDIIGQLE PMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGDSRIILTNSAEEALLKPNVAYTFFSSK YVKKINKAVEAVIFL SWAEELVYDFTDETNEVTTMDKIADITIIVPYIGPALNIGNMVSKGEFVEAILFTGVVAL LEFIPEYSLPVFGTF AIVSYIANKVLTVQTINNALSKRNEKWDEVYKYTVTNWLAKVNTQIDLIREKMKKALENQ AEATRAIINYQYNQY TEEEKNNINFNIDDLSSKLNRSINRAMININKFLDQCSVSYLMNSMIPYAVKRLKDFDAS VRDVLLKYIYDNRGT LILQVDRLKDEVNNTLSADIPFQLSKYVNDKKLLSTFTEYIKNIVNTSILSIVYKKDDLI DLSRYGAKINIGDRV YYDSIDKNQIKLINLESSTIEVILKNAIVYNSMYENFSTSFWIKIPKYFSKINLNNEYTI INCIENNSGWKVSLN YGEIIWTLQDNKQNIQRVVFKYSQMVNISDYINRWMFVTITNNRLTKSKIYINGRLIDQK PISNLGNIHASNKIM FKLDGCRDPRRYIMIKYFNLFDKELNEKEIKDLYDSQSNPGILKDFWGNYLQYDKPYYML NLFDPNKYVDVNNIG IRGYMYLKGPRGSVMTTNIYLNSTLYMGTKFIIKKYASGNEDNIVRNNDRVYINVVVKNK EYRLATNASQAGVEK ILSALEIPDVGNLSQVVVMKSKDDQGIRNKCKMNLQDNNGNDIGFVGFHLYDNIAKLVAS NWYNRQVGKASRTFG CSWEFIPVDDGWGESSL The endogenous activation loop is dash-underlined. SEQ ID NO: 94 (BoNT/A4 – GenBank Accession No. EU341307.1) MPLVNQQINYYDPVNGVDIAYIKIPNAGKMQPVKAFKIHNKVWVIPERDIFTNPEEVDLN PPPEAKQVPISYYDS AYLSTDNEKDNYLKGVIKLFERIYSTDLGRMLLISIVRGIPFWGGGKIDTELKVIDTNCI NIIQLDDSYRSEELN LAIIGPSANIIESQCSSFRDDVLNLTRNGYGSTQYIRFSPDFTVGFEESLEVDTNPLLGA GKFAQDPAVALAHEL IHAEHRLYGIAINTNRVFKVNTNAYYEMAGLEVSLEELITFGGNDAKFIDSLQKKEFSLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDATGKFLVDRLKFDELYKLLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPDVNYTIHDGFNLRNTNLAANFNGQNIEINNKNFDKLKNFTGLFEFYKLLCVRGII TSKTKSLDEGYNKAL NELCIKVNNWDLFFSPSEDNFTNDLDKVEEITSDTNIEAAEENISLDLIQQYYLNFNFDN EPENTSIENLSSDII GQLEPMPNIERFPNGKKYELNKYTMFHYLRAQEFKHSNSRIILTNSAKEALLKPNIVYTF FSSKYIKAINKAVEA VTFVNWIENLVYDFTDETNEVSTMDKIADITIVIPYIGPALNIGNMIYKGEFVEAIIFSG AVILLEIVPEIALPV LGTFALVSYVSNKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAIVNTQINLIREKMKKA LENQAEATKAIINYQ YNQYTEEEKNNINFNIDDLSSKLNESINSAMININKFLDQCSVSYLMNSMIPYAVKRLKD FDASVRDVLLKYIYD NRGTLIGQVNRLKDKVNNTLSADIPFQLSKYVDNKKLLSTFTEYIKNITNASILSIVYKD DDLIDLSRYGAEIYN GDKVYYNSIDKNQIRLINLESSTIEVILKKAIVYNSMYENFSTSFWIRIPKYFNSISLNN EYTIINCMENNSGWK VSLNYGEIIWTFQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRITKSKIYINGRL IDQKPISNLGNIHAS NKIMFKLDGCRDPHRYIVIKYFNLFDKELSEKEIKDLYDNQSNSGILKDFWGDYLQYDKS YYMLNLYDPNKYVDV NNVGIRGYMYLKGPRDNVMTTNIYLNSSLYMGTKFIIKKYASGNKDNIVRNNDRVYINVV VKNKEYRLATNASQA GVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAK LVASNWYNRQIERSS RTLGCSWEFIPVDDGWRERPL The endogenous activation loop is dash-underlined. SEQ ID NO: 95 (BoNT/A5 – GenBank Accession No. EU679004.1) MLFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTELGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHDVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGEHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPEVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGII TSKTKSLDEGYNKAL NDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDN EPENISIENLSSDII GQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIVLTNSVNEALLNPSSVYTF FSSDYVRKVNKATEA AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG AVILLEFIPEIAIPV LGTFALVSYIANKVLTVQTIDNALSKRNEKWGEVYKYIVTNWLAKVNTQIDLIRKKMKEA LENQAEATKAIINYQ YNQYTEEEKNNINFNIGDLSSKLNDSINKAMININKFLNQCSVSYLMNSMIPYGVKRLED FDASLKDALLKYIYD NRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYES NHLIDLSRYASEINI GSKVNFDPIDKNQIQLFNLESSKIEIILKNAIVYNSMYENFSTSFWIKIPKYFSKINLNN EYTIINCIENNSGWK VSLNYGEIIWTLQDNKQNIQRVVFKYSQMVAISDYINRWIFITITNNRLNNSKIYINGRL IDQKPISNLGNIHAS NNIMFKLDGCRDPHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGNYLQYDKP YYMLNLYDPNKYVDV NNVGIRGYMYLKGPRGSIVTTNIYLNSSLYMGTKFIIKKYASGNKDNIVRNNDRVYINVV VKNKEYRLATNASQA GVEKILSVLEIPDVGNLSQVVVMKSKNDQGIRNKCKMNLQDNNGNDIGFIGFHQFNNIDK LVASNWYNRQIERSS RTFGCSWEFIPVDDGWGESPL The endogenous activation loop is dash-underlined. SEQ ID NO: 96 (BoNT/A6 – GenBank Accession No. FJ981696.1) MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFAKLKNFTGLFEFYKLLCVRGII TSKTKSLDKGYNKAL NDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDN EPENISIENLSSDII GQLELMPNIERFPNGKKYELDKYTMFHYLSAQEFEHGKSRIDLTNSVNEALLNPSHVYTF FSSDYVKKVNKATEA AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG AVILLEFIPEIAIPV LGTFAIVSYIANKVLTVQTINNALSKRNEKWDEVYKYTVTNWLAKVNTQIDLIREKMKKA LENQAEATKAIINYQ YNQYTEEEKNNINFNIDDLSSKLNESINSAMININKFLDQCSVSYLMNSMIPYAVKRLKD FDASVRDVLLKYIYD NRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILSLRYEN NHLIDLSRYASKINI GSRVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIKIPKYFSEISLNN EYTIINCIENNSGWK VSLNYGEIIWTLQDNKQNIQRVVFKYSQMVAISDYINRWIFITITNNRLTKSKIYINGRL IDQKPISNLGNIHAS NKIMFKLDGCRDPRRYIMIKYFNLFDKELNEKEIKDLYDSQSNSGILKDFWGNYLQYDKP YYMLNLFDPNKYVDV NNVGIRGYMYLKGSRSTLLTTNIYLNSGLYMGTKFIIKKYASGNKDNIVRNNDRVYINVV VNNKEYRLATNASQA GVEKILSALEIPDIGNLSQVVVMKSKNDQGIRNKCKMNLQDNNGNDIGFIGFHKFNDIYK LVASNWYNRQIEISS RTFGCSWEFIPVDDGWGEKPL The endogenous activation loop is dash-underlined. SEQ ID NO: 97 (BoNT/A7 – GenBank Accession No. JQ954969.1) MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDIFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIINFECKSFGHDVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFAIDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKEVASILNKA KSIIGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLRFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK MNIVPEVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGII TSKTKSLDEGYNKAL NDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISSDLIQQYYLTFNFDN EPENISIENLSSDII GQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEYGNSRIVLINSVNEALLNPSSVYTF FSSDYVKKANEATEA AMFLGWVEQLVYDFTDETSEVSTMDKIADITIIVPYIGPALNIGNMVYKKKFEEALIFSG AVILLEFVPEIVLPI LGTFALVSYTSNKVLTVRTIDNALSKRNEKWEEVYKYIVTNWLAKVNTQINLIRKKMKEA LENQAEATKAIINYQ YNQYTEEEKNNINFNIGDLSSKLNDSINKAMININKFLDQCSVSYLMNSMIPQGVKQLKD FDTSLRDSLLKYIYD NRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYADNQRLLSTFTEYIKNIINTSILNLRYES NHLIDLSRYASKINI GSRVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIKIPKYFSKINLNN EYTIINCIENNSGWK VSLNYGEIIWTLQDNEQNIQRVVFKYSQMVNISDYINRWIFVTITNNRLTKSKIYINGRL IDQKPISNLGNIHAS NKIMFKLDGCRDPHRYILIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKP YYMLNLYDPNKYIDV NNIGIRGYMYLKGPRGSVTTTNIYLNSMLYMGTKFIIKKHASGNKDNIVRNNDRVYINVL VKNKEYRLATNASQA GGEKILSAVEIPDVGNLSQVVVMKSKNDQGIRNKCKMNLQDNNGNDIGFIGFHQFNNIAK LVASNWYNRQIGKTS VTLGCSWELIPVDYGWGESSL The endogenous activation loop is dash-underlined. SEQ ID NO: 98 (BoNT/A8 – GenBank Accession No. KM233166.1) MPFVNKQFNYKDTVNGIDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPKEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHDVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAEHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHNAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPDENYTIKDGFNLKNTNLAANFNGQNTEINSRNFTKLKNFTGLFEFYKLLCVRGII PFKTKSLDEGYNKAL NDLCIKVNNWDLFFSPSEDNFTNDLDKVEEITSDTNIEAAEENISLDLIQQYYLTFDFDN EPENISIENLSSDII GQLEPMPNIERFPNGKKYELDKYTMFHYLRAQEFEHSKSRIALTNSVNEALLNPSRVYTF FSSDYVKKVNKATEA AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG AVILLEFIPEIAIPV LGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLVRKKMKEA LENQAEATKAIINYQ YNQYTEEEKNNINFNIDDLSSKLNESINSAMTNINKFLDQCSVSYLMNSMIPYAVKRLKD FDASVREVLLKYIYD NRGTLILQVDRLKDKVNNTLSADIPFQLSKYVDNKKLLSTFTEYIKNITNTSILSIVVDK DGRLIDLSRYGAEIY NGDKVSYNSIDKNQIKLINLESSAIEVILKNAIVYNSMYENFSTSFWIKIPKYFSKINLN NEYTIINCIENNSGW KVSLNYGEIIWTLQDNQQNIQRVVFKYSQMVNISDYINRWIFVTITNNRLDKSKIYINGR LIDQKPISNLGNIHA SNNIMFKLDGCRDPRRYIVIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDK PYYMLNLYDPNKYVD VNNIGIRGYMYLKGPRGSVVTTNIYLNSTLYMGTKFIIKKYASGNKDNIVRNNDRVYINV VVKNKEYRLATNALQ AGVEKILSALEIPDVGNLSQVVVMKSKNDQGIRNKCKMNLQDNNGNDIGLIGFHQFNNIA KLVASNWYNRQVGKA SRTFGCSWEFIPVDDGWGESSQ The endogenous activation loop is dash-underlined. SEQ ID NO: 99 (BoNT/B1 - UniProt P10844) MPVTINNFNYNDPIDNNNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYDPDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLG DRRVPLEEFNTNIASVTVNKLISNPGEVERKKGIFANLIIFGPGPVLNENETIDIGIQNH FASREGFGGIMQMKFCPEYVSVFNNVQENKGASIFNRRGYFSDPALILMHELIHVLHGLY GIKVDDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPSIITPSTDKSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFSDSLPPVKIKNLLDNEIYTIEEGFNISDKDMEKEYRGQNKAINKQA YEEISKEHLAVYKIQMCKSVKAPGICIDVDNEDLFFIADKNSFSDDLSKNERIEYNTQSN YIENDFPINELILDTDLISKIELPSENTESLTDFNVDVPVYEKQPAIKKIFTDENTIFQY LYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVVEAGLFAGWVKQIVND FVIEANKSNTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLI PVVGAFLLESYIDNKNKIIKTIDNALTKRNEKWSDMYGLIVAQWLSTVNTQFYTIKEGMY KALNYQAQALEEIIKYRYNIYSEKEKSNINIDFNDINSKLNEGINQAIDNINNFINGCSV SYLMKKMIPLAVEKLLDFDNTLKKNLLNYIDENKLYLIGSAEYEKSKVNKYLKTIMPFDL SIYTNDTILIEMFNKYNSEILNNIILNLRYKDNNLIDLSGYGAKVEVYDGVELNDKNQFK LTSSANSKIRVTQNQNIIFNSVFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCMKNNS GWKISIRGNRIIWTLIDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLNNAKIYING KLESNTDIKDIREVIANGEIIFKLDGDIDRTQFIWMKYFSIFNTELSQSNIEERYKIQSY SEYLKDFWGNPLMYNKEYYMFNAGNKNSYIKLKKDSPVGEILTRSKYNQNSKYINYRDLY IGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYTYKYFKKEEEKLFLAPISD SDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFEEYKDYFCIS KWYLKEVKRKPYNLKLGCNWQFIPKDEGWTE The endogenous activation loop is dash-underlined. SEQ ID NO: 100 (BoNT/B2 – GenBank Accession No. AB084152.1) MPVTINNFNYNDPIDNNNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGEVER KKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVDDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPSIITPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFS DSLPPVKIKNLLDNEIYTIEEGFNISDKNMEKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVRAPGICIDVD NEDLFFIADKNSFSDDLSKNERIEYDTQSNYIENRSSIDELILDTNLISKIELPSENTES LTDFNVDVPVYEKQP AIKKIFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVV EAGLFAGWVKQIVDD FVIEANKSSTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLI PVVGAFLLESYIDNK NKIIKTIDNALTKRDEKWIDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEKEKSNIN IDFNDINSKLNEGINQAVDNINNFINECSVSYLMKKMIPLAVEKLLDFDNTLKKNLLNYI DENKLYLIGSAEYEK SKVDKHLKTIIPFDLSMYTNNTILIEIFNKYNSEILNNIILNLRYRDNNLIDLSGYGANV EVYDGVELNDKNQFK LTSSTNSEIRVTQNQNIIFNSMFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCIKNNS GWKISIRGNRIIWTL TDINGKTKSVFFEYSIREDISDYINRWFFVTITNNSDNAKIYINGKLESNIDIKDIGEVI ANGEIIFKLDGDIDR TQFIWMKYFSIFNTELSQSNIKEIYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYI KLKKDSSVGEILTRS KYNQNSNYINYRNLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNSNREWRVYAYKD FKEEEKKLFLANIYD SNEFYKTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVLKDYKNYFCIS KWYLKEVKRKPYNPN LGCNWQFIPKDEGWIE The endogenous activation loop is dash-underlined. SEQ ID NO: 101 (BoNT/B3 – GenBank Accession No. EF028400.1) MPVTINNFNYNDPIDNDNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGEVER KKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVDDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPRIITPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFS DSLPPVKIKNLLDNEIYTIEEGFNISDKNMEKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVRAPGICIDVD NEDLFFIADKNSFSDDLSKNERIEYDTQSNYIENRSSIDELILDTNLISKIELPSENTES LTDFNVDVPVYEKQP AIKKIFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVV EAGLFAGWVKQIVDD FVIEANKSSTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLI PVVGAFLLESYIDNK NKIIKTIDNALTKRDEKWIDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEKEKSNIN IDFNDINSKLNEGINQAIDNINNFINECSVSYLMKKMIPLAVEKLLDFDNTLKKNLLNYI DENKLYLIGSAEYEK SKVDKHLKTIIPFDLSMYTNNTILIEIFNKYNSEILNNIILNLRYRDNNLIDLSGYGAKV EVYNGVELNDKNQFK LTSSANSKIRVTQNQDIIFNSMFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCIKNNS GWKISIRGNKIIWTL TDINGKTKSVFFEYSIRKDVSEYINRWFFVTITNNSDNAKIYINGKLESNIDIKDIGEVI ANGEIIFKLDGDIDR TQFIWMKYFSIFNTELSQSNIKEIYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYI KLKKDSSVGEILTRS KYNQNSNYINYRNLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYAYKD FKKKEEKLFLANIYD SNEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFKDYKDYFCIS KWYLKEVKRKPYNPN LGCNWQFIPKDEGWIE The endogenous activation loop is dash-underlined. SEQ ID NO: 102 (BoNT/B4 – GenBank Accession No. EF051570.1) MPVTINNFNYNDPIDNDNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGEVEQ KKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVDDLPIVPNEKKFFMQSTDTIQAEELYTFGGQDPSIISPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFNKLYKSLMFGFTEIN IAENYKIKTRASYFS DSLPPVKIKNLLDNEIYTIEEGFNISDKNMGKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVKVPGICIDVD NENLFFIADKNSFSDDLSKNERVEYNTQNNYIGNDFPINELILDTDLISKIELPSENTES LTDFNVDVPVYEKQP AIKKVFTDENTIFQYLYSQTFPLNIRDISLTSSFDDALLVSSKVYSFFSMDYIKTANKVV EAGLFAGWVKQIVDD FVIEANKSSTMDKIADISLIVPYIGLALNVGDETAKGNFESAFEIAGSSILLEFIPELLI PVVGVFLLESYIDNK NKIIKTIDNALTKRVEKWIDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEEEKSNIN INFNDINSKLNDGINQAMDNINDFINECSVSYLMKKMIPLAVKKLLDFDNTLKKNLLNYI DENKLYLIGSVEDEK SKVDKYLKTIIPFDLSTYTNNEILIKIFNKYNSEILNNIILNLRYRDNNLIDLSGYGAKV EVYDGVKLNDKNQFK LTSSADSKIRVTQNQNIIFNSMFLDFSVSFWIRIPKYRNDDIQNYIHNEYTIINCMKNNS GWKISIRGNRIIWTL IDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLDNAKIYINGTLESNMDIKDIGEVI VNGEITFKLDGDVDR TQFIWMKYFSIFNTQLNQSNIKEIYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYI KLVKDSSVGEILIRS KYNQNSNYINYRNLYIGEKFIIRRKSNSQSINDDIVRKEDYIHLDFVNSNEEWRVYAYKN FKEQEQKLFLSIIYD SNEFYKTIQIKEYDEQPTYSCQLLFKKDEESTDDIGLIGIHRFYESGVLRKKYKDYFCIS KWYLKEVKRKPYKSN LGCNWQFIPKDEGWTE The endogenous activation loop is dash-underlined. SEQ ID NO: 103 (BoNT/B5 – GenBank Accession No. EF033130.1) MPVTINNFNYNDPIDNNNIIMMEPPFARGMGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGEVER KKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVNDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPSIISPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFS DSLPPVKIKNLLDNEIYTIEEGFNISDKNMEKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVKAPGICIDVD NEDLFFIADKNSFSDDLSKNERIAYNTQNNYIENDFSINELILDTDLISKIELPSENTES LTDFNVYVPVYKKQP AIKKIFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVV EAGLFAGWVKQIVDD FVIEANKSSTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLI PVVGAFLLESYIDNK NKIIETINSALTKRDEKWIDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEKERSNIN IDFNDVNSKLNEGINQAIDNINNFINECSVSYLMKKMIPLAVEKLLDFDNTLRKNLLNYI DENKLYLIGSAEYEK SKVDKYLKTSIPFDLSTYTNNTILIEIFNKYNSDILNNIILNLRYRDNKLIDLSGYGAKV EVYDGVKLNDKNQFK LTSSANSKIRVIQNQNIIFNSMFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCMKNNS GWKISIRGNMIIWTL IDINGKIKSVFFEYSIKEDISEYINRWFFVTITNNSDNAKIYINGKLESHIDIRDIREVI ANDEIIFKLDGNIDR TQFIWMKYFSIFNTELSQSNIEEIYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYI KLKKDSSVGEILTRS KYNQNSKYINYRDLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYMYKY FKKEEEKLFLAPISD SDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFKEYKDYFCIS KWYLKEVKRKPYNSK LGCNWQFIPKDEGWTE The endogenous activation loop is dash-underlined. SEQ ID NO: 104 (BoNT/B6 – GenBank Accession No. AB302852.1) MPVTINNFNYNDPIDNNNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGEVER KKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVDDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPSIITPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFS DSLPPVKIKNLLDNEIYTIEEGFNISDKNMEKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVRAPGICIDVD NEDLFFIADKNSFSDDLSKNERIEYDTQSNYIENRSSIDELILDTNLISKIELPSENTES LTDFNVDVPVYEKQP AIKKFFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVV EAGLFAGWVKQIVDD FVIEANKSNTMDKLADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLI PVVGAFLLESYIDNK NKIIKTIDNALTKRDEKWRDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEKEKSNIN IDFNDINSKLNEGINQAIDNINNFINECSVSYLMKKMIPLAVEKLLDFDNTLKKNLLNYI DENKLYLIGSAEYEK SKVDKHLKTIIPFDLSMYTNNTILIEIFKKYNSEILNNIILNLRYRDNNLIDLSGYGANV EVYDGVELNDKNQFK LTSSTNSEIRVTQNQNIIFNSMFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCIKNNS GWKISIRGNRIIWTL TDINGKTKSVFFEYSIREDISDYINRWFFVTITNNSDNAKIYINGKLESNIDIKDIGEVI ANGEIIFKLDGDIDR TQFIWMKYFSIFNTELSQSNIKEIYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYI KLKKDSPVGEILTRS KYNQNSNYINYRNLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYALKN FKKKEEKLFLAPISD SDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFKDYKYYFCIS KWYLKEVKRKPYNPN LGCNWQFIPKDEGWIE The endogenous activation loop is dash-underlined. SEQ ID NO: 105 (BoNT/B7 – GenBank Accession No. JQ354985.1) MPVTINNFNYNDPIDNNNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGEVER KKGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVDDLPIVPNEKKFFMQSTDAIQAEELYTFGGQDPSIITPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFS DSLPPVKIKNLLDNEIYTIEEGFNISDKDMEKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVKAPGICIDVD NEDLFFIADKNSFSDDLSKNERIEYNTKNIYIENYFSINELILDTDLISGIELPSENTES LTDFNVDVPVYEKQP AIKKIFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVV EAGLFAGWVKQIIDD FVIEANKSSTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGASILLEFIPELLI PVVGAFLLESYIDNK NKIIKTIDNALTKRVEKWIDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEKEKLNIN IDFNDINSKLNEGINQAIDNINNFINECSVSYLMKKMIPLAIEKLLDFDNALKKNLLNYI DENKLYLIGSVEEEK SKVDKFFKTIIPFDLSMYTNNTILIEMVNKYNSEILNNIILNLRYRDNNLIDSSGYGAKV EVYNGVELNDKNQFK LTSSANSKIKVTQNQNITFNSMFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCMKNNS GWKISIRGNRIIWTL TDINGKTKSVFFEYSIREDISDYINRWFFVTITNNLDNAKIYINGKLESNIDIRDIREVI VNGEIIFKLDGEIDR TQFIWMKYFSIFNTELSQSNVKEIYKIQSYSKYLKDFWGNPLMYNKEYYMFNAGNKNSYI KLVKDSSVGEILTRS KYNQNSNYINYRNLYIGEKFIIRRKSSSQSISDDIVRKEDYIYLDFFNSNREWRVYAYKN FKGQEEKLFLANIYD SNEFYKTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHNFYESGILFKDYKDYFCIS KWYLKEVKKKPYSSN LGCNWQFIPKDEGWTE The endogenous activation loop is dash-underlined. SEQ ID NO: 106 (BoNT/B8 – GenBank Accession No. JQ964806.1) MPVTINNFNYNDPIDNNNIIMMEPPFARGTGRYYKAFKITDRIWIIPERYTFGYKPEDFN KSSGIFNRDVCEYYD PDYLNTNDKKNIFLQTMIKLFNRIKSKPLGEKLLEMIINGIPYLGDRRVPLEEFNTNIAS VTVNKLISNPGGEER KEGIFANLIIFGPGPVLNENETIDIGIQNHFASREGFGGIMQMKFCPEYVSVFNNVQENK GASIFNRRGYFSDPA LILMHELIHVLHGLYGIKVDDLPIVPNGKKFFMQSTDAIQAEELYTFGGQDPSIITPSTD KSIYDKVLQNFRGIV DRLNKVLVCISDPNININIYKNKFKDKYKFVEDSEGKYSIDVESFDKLYKSLMFGFTETN IAENYKIKTRASYFS DSLPPVKIKNLLDDEIYTIEEGFNISDKNMGKEYRGQNKAINKQAYEEISKEHLAVYKIQ MCKSVRAPGICIDVD NEDLFFIADKNSFSDDLSKNERIEYNTQSNYIENDFSINELILDTDLISKIELPSENTES LTDFNVDVPVYEKQP AIKKIFTDENTIFQYLYSQTFPLDIRDISLTSSFDDALLFSNKVYSFFSMDYIKTANKVV EAGLFAGWVKQIVDD FVIEANKSNTMDKIADISLIVPYIGLALNVGNETAKGNFENAFEIAGSSILLEFIPELLI PVVGAFLLESYIDNK NKIIKTIDNALTKRDEKWIDMYGLIVAQWLSTVNTQFYTIKEGMYKALNYQAQALEEIIK YKYNIYSEKEKSNIS IDFNDINSKLNEGINQAIDNINDFINECSVSYLMKKMIPLAVEKLLDFDNTLKKNLLNYI DENKLYLIGSAEYEK SKVDKHLKTIMTFDLSMYTNNTILIKMVNKYNSEILNNIILNLRYRDNNLIDLSGYGANV EVYDGVELNDKNQFK LTSSTNSEIRVTQNQNIIVNSMFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCMKNNS GWKISIRGNRIIWTL IDINGKIKSVFFEYSIRKDVSEYINRWFFVTITNNLDNAKIYINGKLESNMDIRDIREVI ANGEIIFKLDGDIDR TQFIWMKYFSIFNTELSQSNIEEIYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGSKNSYI KLKKDSSVGEILTRS KYNQNSQYINYRDLYIGEKFIIKRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYAYKD FKGQKEQKLFLANIH DSNEFYKTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGFVFQEYKYYFCI SKWYLKEVKKKPYNP DLGCNWQFIPKDEGWTE The endogenous activation loop is dash-underlined. SEQ ID NO: 107 (BoNT/C1 - UniProt P18640) MPITINNFNYSDPVDNKNILYLDTHLNTLANEPEKAFRITGNIWVIPDRFSRNSNPNLNK PPRVTSPKSGYYDPNYLSTDSDKDTFLKEIIKLFKRINSREIGEELIYRLSTDIPFPGNN NTPINTFDFDVDFNSVDVKTRQGNNWVKTGSINPSVIITGPRENIIDPETSTFKLTNNTF AAQEGFGALSIISISPRFMLTYSNATNDVGEGRFSKSEFCMDPILILMHELNHAMHNLYG IAIPNDQTISSVTSNIFYSQYNVKLEYAEIYAFGGPTIDLIPKSARKYFEEKALDYYRSI AKRLNSITTANPSSFNKYIGEYKQKLIRKYRFVVESSGEVTVNRNKFVELYNELTQIFTE FNYAKIYNVQNRKIYLSNVYTPVTANILDDNVYDIQNGFNIPKSNLNVLFMGQNLSRNPA LRKVNPENMLYLFTKFCHKAIDGRSLYNKTLDCRELLVKNTDLPFIGDISDVKTDIFLRK DINEETEVIYYPDNVSVDQVILSKNTSEHGQLDLLYPSIDSESEILPGENQVFYDNRTQN VDYLNSYYYLESQKLSDNVEDFTFTRSIEEALDNSAKVYTYFPTLANKVNAGVQGGLFLM WANDVVEDFTTNILRKDTLDKISDVSAIIPYIGPALNISNSVRRGNFTEAFAVTGVTILL EAFPEFTIPALGAFVIYSKVQERNEIIKTIDNCLEQRIKRWKDSYEWMMGTWLSRIITQF NNISYQMYDSLNYQAGAIKAKIDLEYKKYSGSDKENIKSQVENLKNSLDVKISEAMNNIN KFIRECSVTYLFKNMLPKVIDELNEFDRNTKAKLINLIDSHNIILVGEVDKLKAKVNNSF QNTIPFNIFSYTNNSLLKDIINEYFNNINDSKILSLQNRKNTLVDTSGYNAEVSEEGDVQ LNPIFPFDFKLGSSGEDRGKVIVTQNENIVYNSMYESFSISFWIRINKWVSNLPGYTIID SVKNNSGWSIGIISNFLVFTLKQNEDSEQSINFSYDISNNAPGYNKWFFVTVTNNMMGNM KIYINGKLIDTIKVKELTGINFSKTITFEINKIPDTGLITSDSDNINMWIRDFYIFAKEL DGKDINILFNSLQYTNVVKDYWGNDLRYNKEYYMVNIDYLNRYMYANSRQIVFNTRRNNN DFNEGYKIIIKRIRGNTNDTRVRGGDILYFDMTINNKAYNLFMKNETMYADNHSTEDIYA IGLREQTKDINDNIIFQIQPMNNTYYYASQIFKSNFNGENISGICSIGTYRFRLGGDWYR HNYLVPTVKQGNYASLLESTSTHWGFVPVSE The endogenous activation loop is dash-underlined. SEQ ID NO: 108 (BoNT/D - UniProt P19321) MTWPVKDFNYSDPVNDNDILYLRIPQNKLITTPVKAFMITQNIWVIPERFSSDTNPSLSK PPRPTSKYQSYYDPSYLSTDEQKDTFLKGIIKLFKRINERDIGKKLINYLVVGSPFMGDS STPEDTFDFTRHTTNIAVEKFENGSWKVTNIITPSVLIFGPLPNILDYTASLTLQGQQSN PSFEGFGTLSILKVAPEFLLTFSDVTSNQSSAVLGKSIFCMDPVIALMHELTHSLHQLYG INIPSDKRIRPQVSEGFFSQDGPNVQFEELYTFGGLDVEIIPQIERSQLREKALGHYKDI AKRLNNINKTIPSSWISNIDKYKKIFSEKYNFDKDNTGNFVVNIDKFNSLYSDLTNVMSE VVYSSQYNVKNRTHYFSRHYLPVFANILDDNIYTIRDGFNLTNKGFNIENSGQNIERNPA LQKLSSESVVDLFTKVCLRLTKNSRDDSTCIKVKNNRLPYVADKDSISQEIFENKIITDE TNVQNYSDKFSLDESILDGQVPINPEIVDPLLPNVNMEPLNLPGEEIVFYDDITKYVDYL NSYYYLESQKLSNNVENITLTTSVEEALGYSNKIYTFLPSLAEKVNKGVQAGLFLNWANE VVEDFTTNIMKKDTLDKISDVSVIIPYIGPALNIGNSALRGNFNQAFATAGVAFLLEGFP EFTIPALGVFTFYSSIQEREKIIKTIENCLEQRVKRWKDSYQWMVSNWLSRITTQFNHIN YQMYDSLSYQADAIKAKIDLEYKKYSGSDKENIKSQVENLKNSLDVKISEAMNNINKFIR ECSVTYLFKNMLPKVIDELNKFDLRTKTELINLIDSHNIILVGEVDRLKAKVNESFENTM PFNIFSYTNNSLLKDIINEYFNSINDSKILSLQNKKNALVDTSGYNAEVRVGDNVQLNTI YTNDFKLSSSGDKIIVNLNNNILYSAIYENSSVSFWIKISKDLTNSHNEYTIINSIEQNS GWKLCIRNGNIEWILQDVNRKYKSLIFDYSESLSHTGYTNKWFFVTITNNIMGYMKLYIN GELKQSQKIEDLDEVKLDKTIVFGIDENIDENQMLWIRDFNIFSKELSNEDINIVYEGQI LRNVIKDYWGNPLKFDTEYYIINDNYIDRYIAPESNVLVLVQYPDRSKLYTGNPITIKSV SDKNPYSRILNGDNIILHMLYNSRKYMIIRDTDTIYATQGGECSQNCVYALKLQSNLGNY GIGIFSIKNIVSKNKYCSQIFSSFRENTMLLADIYKPWRFSFKNAYTPVAVTNYETKLLS TSSFWKFISRDPGWVE The endogenous activation loop is dash-underlined. SEQ ID NO: 109 (BoNT/CD – GenBank Accession No. AB200360.1) MPITINNFNYSDPVDNKNILYLDTHLNTLANEPEKAFRIIGNIWVIPDRFSRDSNPNLNK PPRVTSPKSGYYDPN YLSTDSEKDTFLKEIIKLFKRINSREIGEELIYRLATDIPFPGNNNTPINTFDFDVDFNS VDVKTRQGNNWVKTG SINPSVIITGPRENIIDPETSTFKLTNNTFAAQEGFGALSIISISPRFMLTYSNATNNVG EGRFSKSEFCMDPIL ILMHELNHAMHNLYGIAIPNDQRISSVTSNIFYSQYNVKLEYAEIYAFGGPTIDLIPKSA RKYFEEKALDYYRSI AKRLNSITTANPSSFNKYIGEYKQKLIRKYRFVVESSGEVAVDRNKFAELYKELTQIFTE FNYAKIYNVQNRKIY LSNVYTPVTANILDDNVYDIQNGFNIPKSNLNVLFMGQNLSRNPALRKVNPENMLYLFTK FCHKAIDGRSLYNKT LDCRELLVKNTDLPFIGDISDIKTDIFLSKDINEETEVIDYPDNVSVDQVILSKNTSEHG QLDLLYPIIEGESQV LPGENQVFYDNRTQNVDYLNSYYYLESQKLSDNVEDFTFTTSIEEALDNSGKVYTYFPKL ADKVNTGVQGGLFLM WANDVVEDFTTNILRKDTLDKISDVSAIIPYIGPALNISNSVRRGNFTEAFAVTGVTILL EAFQEFTIPALGAFV IYSKVQERNEIIKTIDNCLEQRIKRWKDSYEWMIGTWLSRITTQFNNISYQMYDSLNYQA DAIKDKIDLEYKKYS GSDKENIKSQVENLKNSLDIKISEAMNNINKFIRECSVTYLFKNMLPKVIDELNKFDLKT KTELINLIDSHNIIL VGEVDRLKAKINESFENTIPFNIFSYTNNSLLKDIINEYFNSINDSKILSLQNKKNALVD TSGYNAEVRLEGDVQ VNTIYTNDFKLSSSGDKIIVNLNNNILYSAIYENSSVSFWIKISKDLTNSHNEYTIINSI KQNSGWKLCIRNGNI EWILQDINRKYKSLIFDYSESLSHTGYTNKWFFVTITNNIMGYMKLYINGELKQSERIED LDEVKLDKTIVFGID ENIDENQMLWIRDFNIFSKELSNEDINIVYEGQILRNVIKDYWGNPLKFDTEYYMINYNY IDRYIAPKNNILVLV QYSDISKLYTKNPITIKSAANKNPYSRILNGDDIMFHMLYDSREYMIIRDTDTIYATQGG QCSKNCVYALKLQSN LGNYGIGIFSIKNIVSQNKYCSQIFSSFMKNTMLLADIYKPWRFSFENAYTPVAVTNYET KLLSTSSFWKFISRD PGWVE The endogenous activation loop is dash-underlined. SEQ ID NO: 110 (BoNT/DC – GenBank Accession No. AB745660.1) MTWPVKDFNYSDPVNDNDILYLRIPQNKLITTPVKAFMITQNIWVIPERFSSDTNPSLSK PPRPTSKYQSYYDPS YLSTDEQKDTFLKGIIKLFKRINERDIGKKLINYLVVGSPFMGDSSTPEDTFDFTRHTTN IAVEKFENGSWKVTN IITPSVLIFGPLPNILDYTASLTLQGQQSNPSFEGFGTLSILKVAPEFLLTFSDVTSNQS SAVLGKSIFCMDPVI ALMHELTHSLHQLYGINIPSDKRIRPQVSEGFFSQDGPNVQFEELYTFGGSDVEIIPQIE RLQLREKALGHYKDI AKRLNNINKTIPSSWSSNIDKYKKIFSEKYNFDKDNTGNFVVNIDKFNSLYSDLTNVMSE VVYSSQYNVKNRTHY FSKHYLPVFANILDDNIYTIINGFNLTTKGFNIENSGQNIERNPALQKLSSESVVDLFTK VCLRLTRNSRDDSTC IQVKNNTLPYVADKDSISQEIFESQIITDETNVENYSDNFSLDESILDAKVPTNPEAVDP LLPNVNMEPLNVPGE EEVFYDDITKDVDYLNSYYYLEAQKLSNNVENITLTTSVEEALGYSNKIYTFLPSLAEKV NKGVQAGLFLNWANE VVEDFTTNIMKKDTLDKISDVSAIIPYIGPALNIGNSALRGNFKQAFATAGVAFLLEGFP EFTIPALGVFTFYSS IQEREKIIKTIENCLEQRVKRWKDSYQWMVSNWLSRITTQFNHISYQMYDSLSYQADAIK AKIDLEYKKYSGSDK ENIKSQVENLKNSLDVKISEAMNNINKFIRECSVTYLFKNMLPKVIDELNKFDLKTKTEL INLIDSHNIILVGEV DRLKAKVNESFENTIPFNIFSYTNNSLLKDMINEYFNSINDSKILSLQNKKNTLMDTSGY NAEVRVEGNVQLNPI FPFDFKLGSSGDDRGKVIVTQNENIVYNAMYESFSISFWIRINKWVSNLPGYTIIDSVKN NSGWSIGIISNFLVF TLKQNENSEQDINFSYDISKNAAGYNKWFFVTITTNMMGNMMIYINGKLIDTIKVKELTG INFSKTITFQMNKIP NTGLITSDSDNINMWIRDFYIFAKELDDKDINILFNSLQYTNVVKDYWGNDLRYDKEYYM INVNYMNRYMSKKGN GIVFNTRKNNNDFNEGYKIIIKRIIGNTNDTRVRGENVLYFNTTIDNKQYSLGMYKPSRN LGTDLVPLGALDQPM DEIRKYGSFIIQPCNTFDYYASQLFLSSNATTNRIGILSIGSYSFKLGDDYWFNHEYLIP VIKIEHYASLLESTS THWVFVPASE The endogenous activation loop is dash-underlined. SEQ ID NO: 111 (BoNT/E - UniProt Q00496) MPKINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTS LKNGDSSYYDPNYLQSDEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTP DNQFHIGDASAVEIKFSNGSQDILLPNVIIMGAEPDLFETNSSNISLRNNYMPSNHRFGS IAIVTFSPEYSFRFNDNCMNEFIQDPALTLMHELIHSLHGLYGAKGITTKYTITQKQNPL ITNIRGTNIEEFLTFGGTDLNIITSAQSNDIYTNLLADYKKIASKLSKVQVSNPLLNPYK DVFEAKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLRTKFQVKCRQTYIGQYKYFKL SNLLNDSIYNISEGYNINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKG IRKSICIEINNGELFFVASENSYNDDNINTPKEIDDTVTSNNNYENDLDQVILNFNSESA PGLSDEKLNLTIQNDAYIPKYDSNGTSDIEQHDVNELNVFFYLDAQKVPEGENNVNLTSS IDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTTEANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERDEKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIE SKYNSYTLEEKNELTNKYDIKQIENELNQKVSIAMNNIDRFLTESSISYLMKIINEVKIN KLREYDENVKTYLLNYIIQHGSILGESQQELNSMVTDTLNNSIPFKLSSYTDDKILISYF NKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNKNQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTFEDNRGINQKLAFNYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNL GNIHVSDNILFKIVNCSYTRYIGIRYFNIFDKELDETEIQTLYSNEPNTNILKDFWGNYL LYDKEYYLLNVLKPNNFIDRRKDSTLSINNIRSTILLANRLYSGIKVKIQRVNNSSTNDN LVRKNDQVYINFVASKTHLFPLYADTATTNKEKTIKISSSGNRFNQVVVMNSVGNCTMNF KNNNGNNIGLLGFKADTVVASTWYYTHMRDHTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 112 (BoNT/E1 – GenBank Accession No. GQ244314.1) MPKINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTS LKNGDSSYYDPNYLQ SDEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGSQDILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTKYTITQKQNPLITNIRGTNIEEFLTFGGTDLNIITSAQSNDIYTNLLADYKKIASK LSKVQVSNPLLNPYK DVFEAKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNDSIYNISEGY NINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKGIRKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKNELT NKYDIKQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLNYIIQHGSILGESQQE LNSMVTDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYSNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNNFIDRRKDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTATTNKEKTIKISSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGLLGFKADTVVASTWYYTHMRDHTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 113 (BoNT/E2 – GenBank Accession No. EF028404.1) MPKINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTS LKNGDSSYYDPNYLQ SDEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGIQDILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTKYTITQKQNPLITNIRGTNIEEFLTFGGTDLNIITSAQSNDIYTNLLADYKKIASK LSKVQVSNPLLNPYK DVFEAKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNDSIYNISEGY NINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKGIRKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKNELT NKYDIKQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLNYIIQHGSILGESQQE LNSMVTDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYNNEPNANILKDFWGNYLLYDKEYYLLNVLKPNNFIDRRTDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTNTTNKEKTIKSSSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGMLGFKDNTLVASTWYYTHMRDNTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 114 (BoNT/E3 – GenBank Accession No. EF028403.1) MPKINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTS LKNGDSSYYDPNYLQ SDEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGSQHILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSINEFIQDPALTL MHELIHSLHGLYGAK GITTTCIITQQQNPLITNRKGINIEEFLTFGGNDLNIITVAQYNDIYTNLLNDYRKIASK LSKVQVSNPQLNPYK DIFQEKYGLDKDASGIYSVNINKFDDILKKLYSFTEFDLATKFQVKCRETYIGQYKYFKL SNLLNDSIYNISEGY NINNLKVNFRGQNANLNPRIIKPITGRGLVKKIIRFCKNIVSVKGIRKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKNELT NKYDIKQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLNYIIQHGSILGESQQE LNSMVTDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYSNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNNFIDRRKDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTATTNKEKTIKISSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGLLGFKADTVVASTWYYTHMRDHTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 115 (BoNT/E4 – GenBank Accession No. AB088207.1) MPTINSFNYNDPVNNRTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQDFLPPTS LKNGDSSYYDPNYLQ SDQEKDKFLKIVTKIFNRINDNLSGRILLEELSKANPYLGNDNTPDGDFIINDASAVPIQ FSNGSQSILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFKDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTKYTITQKQNPLITNIRGTNIEEFLTFGGTDLNIITSAQSNDIYTNLLADYKKIASK LSKVQVSNPLLNPYK DVFEAKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNDSIYNISEGY NINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKGIRKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVGWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNALKAIIESKYNSYTLEEKNELT NKYDIEQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLDYIIKHGSILGESQQE LNSMVIDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNSGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDKKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYNNEPNANILKDFWGNYLLYDKEYYLLNVLKPNNFINRRTDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLLPLYADTATTNKEKTIKISSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGLLGFKADTVVASTWYYTHMRDNTNSNGFFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 116 (BoNT/E5 – GenBank Accession No. AB037711.1) MPKINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTS LKNGDSSYYDPNYLQ SDEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGSQDILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTKYTITQKQNPLITNIRGTNIEEFLTFGGTDLNIITSAQSNDIYTNLLADYKKIASK LSKVQVSNPLLNPYK DVFEAKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNDSIYNISEGY NINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKGIRKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFVPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNALKTIIEFKYNSYTLEEKKELK NNYDIEQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLDYIIQHGSILGESQQE LNSMVIDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGEIFIYPTNK NQFTIFNSKPSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNINNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNARINQKLVF KYGNANGISDYINKWIFVTITNDRLGDSKLYINGHLIDQKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYSNEPNTNILKDFWGNYLLYDKGYYLLNVLKPNNFIDRRKDSTLSINN IRSTILLANRLYSGI KVKIQRVNDSSTNDRFVRKNDQVYINYISNSSSYSLYADTNTTDKEKTIKSSSSGNRFNQ VVVMNSVGNNCTMNF KNNNGNNIGLLGFKADTVVASTWYYTHMRDHTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 117 (BoNT/E6 – GenBank Accession No. AM695759.1) MPTINSFNYNDPVNDRTILYIKPGGCQEFYKSFNIMKNIWIIPERNVIGTTPQDFHPPTS LKNGDSSYYDPNYLQ SYEEKDRFLKIVTKIFNRINNNLSGGILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGSQDILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFKDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTQYTITQQQNPLITNIKGTNIEEFLTFGGTDLNIITSAQYNDIYTNLLADYKKIASK LSKVQVSNPLLNPYK DVFEKKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNNSIYNISEGY NINTLKVNFRGQNTNLNPRIITPLTGRGLVKKIIRFCKNIVFSKGIRKSICIEINNGELF FVASDNSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNIDFTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNALKTIIESKYNSYTLEEKNELT NKYNIEQIENELNQK VSIAMNNIEIFLTESSISYLMKLINEVKINKLREYDENVKTYLLDYIIKHGSILGESQQE LNSMVIDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNNKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNSGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDKKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYNNEPNANILKDFWGNYLLYDKEYYLLNVLKPNNFINRRTDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVDSKTHLLPLYADTATTNKEKTIKISSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGLLGFKADTVVASTWYYTHMRDNTNSNGFFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 118 (BoNT/E7 – GenBank Accession No. JN695729.1) MPKINSFNYNDPVNDKTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQDFLPPTS LKNGDSSYYDPNYLQ SNEEKDRFLKIVTKIFNRINDNLSGRILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGNQSILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK RITTKYTITQQQNPLITNIRGTNIEEFLTFGGTDLNIITSAQYNDIYTNLLADYKKIASK LSKVQVSNPQLNPYK DIFQEKYGLDKNASGIYSVNINKFDDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNNSIYNISEGY NINTLKVNFRGQNTNLNPRIITQLTGRGLVKKIIRFCKNIVFSKGITKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKNELT NKYDIKQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLNYIIQHGSILGESQQE LNSMVTDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYSNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNNFIDRRKDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTATTNKEKTIKISSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGLLGFKADTVVASTWYYTHMRDHTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 119 (BoNT/E8 – GenBank Accession No. JN695730.1) MPKINSFNYNDPVNDKTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQDFLPPTS LKNGDSSYYDPNYLQ SNEEKDRFLKIVTKIFNRINDNLSGRILLEELSKANPYLGNDNTPDNQFHIGDASAVEIK FSNGNQSILLPNVII MGAEPDLFETNSSNISLRNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK RITTKYTITQQQNPLITNIRGTNIEEFLTFGGTDLNIITSAQYNDIYTNLLADYKKIASK LSKVQVSNPQLNPYK DIFQEKYGLDKNASGIYSVNINKFDDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNNSIYNISEGY NINTLKVNFRGQNTNLNPRIITQLTGRGLVKKIIRFCKNIVFSKGITKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSYIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKTVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNALKTIIESKYNSYTLEEKNELT NKYNIEQIENELNQK VSIAMNNIEIFLTESSISYLMKLINEVKINKLREYDENVKTYLLDYIIKHGSILGESQQE LNSMVIDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDKKSILNLGNIHVSDNILFKIVN CSYTRYIGIRYFNIF DKELDETEIQTLYNNEPNANILKDFWGNYLLYDKEYYLLNVLKPNNFIDRRTDSTLSINN IRSTILLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTNTTNKEKTIKSSSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGMLGFKDNTLVASTWYYTHMRDNTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 120 (BoNT/E9 – GenBank Accession No. JX424534.1) MPKINSFNYNDPVNDNTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQNFLPPTS LKNGDSSYYDPNYLQ NDQEKDRFLKIVTKVFNRINDNLSGRILLEELSKANPYLGNDNTRDDDFIINDGSAVPIQ FSNGSQSILLPTVII MGAEPDLFETNSSNVSLINNYSPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL IHELIHSLHGLYGAK GITTKYTITQQQNPLITNIRGINIEEFLTFGGNNLNIITSSQLNDIYTNLLDDYKKIASK LSKVQVSNPQLNPYK DVFQEKYGLDKNASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRETYIGQYKYFKL SNLLNDSIYNISEGY NINTLNVNFRGQNPNLNPRIITPITDRGLVKKIIRFCKNIVSVKGIRKSICIEVNNGDLF FVASEKSYNNDSINI PKEIDDTVTLNNNYENDLDQVILNFNSESAPGLSDKKLNISIQDDVYIPKYDSNGTSDIE QYDVSELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQSKIYTFFSSEFINNVNKPVQAALFVGWIQQVLVDFTT EATQKSTVDKIADIS IVVPYIGLALNIGNESQKGNFKDALELLGAGILLEFVPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWITKINTQFNKRKEQMYQALQNQVNALKTIIESKYNSYTLEEKNELT NKYDIEQIENELNQK VSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLDYITKHGSILGESQQE LNSMIIDTLNNSIPF KLSSYTDDKILISYFNKFFKTIKSSSVLSMRYKNDKYIDTSGYDSNININGDVFIYPTNK NQFGIYNSKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYNNKIVNVNNEYTIINCMRDNNSGWKISLNHNEII WTLQDNAGINQKLVF KYGNANGISDYINKWIFVTITNDRLGYSKLYINGHLIDQKSILNLGNIHVSDNILFKIVN CSYTRYIGMRYFNIF DKELDETEIQTLYNNEPNANVLKDFWGNYLLYNKEYYLLNMLKPSKTISHNRDLTFSIYN NRNIVNGLYRLYSGI KVKIQKINDSDTRDNIVRDNDQVYVNYINGNVYYSLYADTNATNKEKTIKSSTSGNRFNQ VVVMNSVRNNCTMNF KNNNGHDIGLLGFKSNALVASTWYYTNMRDHTNSNGCFWSFIPEENGWQEH The endogenous activation loop is dash-underlined. SEQ ID NO: 121 (BoNT/E10 – GenBank Accession No. KF861917.1) MPKINSFNYNDPVNDKTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQDFLPPTS LKNGDSSYYDPNYLQ SNEEKDRFLKIVTKIFNRINDNLSGGILLEELSKANPYLGNDNTPNNQFHIGDASAVEIK FSNGSQSILLPTVII MGAEPDLFETNSSNISLKNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTKYTITQQQNPLITNIRGTNIEEFLTFGGTDLNIITNAQSNDIYTNLLADYKKIASK LSQVQVSNPQLNPYK DIFQEKYGLDKNASGIYSVNINKFDDIFKKLYSFTEFDLATKFQVKCRQTYIGQYKYFKL SNLLNNSIYNISEGY NINTLKVNFRGQNTNLNPRIITQLTGRGLVKKIIRFCKNIVFSKGITKSICIEINNGELF FVASENSYNDDNINT PKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQNDAYIPKYDSNGTSDIE QHDVNELNVFFYLDA QKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAALFVSWIQQVLVDFTT EANQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPTILVFTIKSFLGSSDNK NKVIKAINNALKERD EKWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNALKTIIESKYNSYTLEEKNELT NKYNIEQIENELNQK VSIAMNNIEIFLTESSISYLMKLINEVKINKLREYDENVKTYLLDYIIKHGSILGESQQE LNSMVIDTLNNSIPF KLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGDVYKYPTNK NQFGIYNDKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLAF NYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDKKSILNLGNIHVSDNILFKIVN CSYTRYIGMRYFNIF DKELDKTEIETLYNNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNNVIDSNRDSTFSIHN IRSTIVLANKLYLGI KVKIQRVNNSSTNDNLVRKNDQVYINFVPIKTHLFPLYADTNTTNKEKTIKSSSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGMLGFKDNTLVASTWYYTHMRDNTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 122 (BoNT/E11 – GenBank Accession No. KF861875.1) MPKINSFNYNDPVNDKTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQDFLPPTS LKNGDSSYYDPNYLQ SNEEKDRFLKIVTKIFNRINDNLSGGILLEELSKANPYLGNDNTPNNQFHIGDASAVEIK FSNGSQSILLPTVII MGAEPDLFETNSSNISLKNNYMPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPALTL MHELIHSLHGLYGAK GITTKYTITQQQNPLITNIRGTNIEEFLTFGGTDLNIITNAQSNDIYTNLLDDYKKIASK LSQVQVSNPQLNPYK DVFQEKYGLDKDANGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRKTYIGHHKYFRL SDLLNDSIYNISDGY NINTLKVNFRGQNTNLNTRIITPITGRGVVRKIIRFCTNIFSPKGIRKSICIEVNNGELF FVASENSYNDDNINT SKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQDDAYIPKYDSNGTSDIE QYDVSELNVFFYLDA QKVPEGENNVDFTSSIDTALLEQPKIYTFFSSKFISNLNKTMQAALFVSWIQQVLVDFTT EATQKSTVDKIADIS IVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFEPELLIPIILVFTIKSFLGSSDNK NKVIKAINNALKERD ENWKEVYSFIVSNWMTKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKNELK NKYDIEQIENELNQT VSIAMNNIEIFLTESSISYLMKLINEVKINKLKEYDENVKTYLLDYIIKHGSILGESQQE LNSMVIDTLNNSIPF KLSSYTDDKILISYFNKFFKTIKSSSVLNMRYKNDKYIDTSGYDSNINIKGDVFIYPTNK NQFGIYNNKLSEVNI SQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHNEII WTLQDNAGINQKLVF KYGNANGISDYINKWIFVTITNDRLGDSKLYINGNLIDKKSILNLGNIHVSDNILFKIVN CSYTRYIGMRYFNIF DKELDKTEIETLYNNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNNVIDSNRDSTFSIHN IRSTIVLANRLYSGI KVKIQRVNNSSTNDNLVRKNDQVYINFVASKTHLFPLYADTNTTNKEKTIKSSSSGNRFN QVVVMNSVGNNCTMN FKNNNGNNIGMLGFKDNTLVASTWYYTHMRDNTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 123 (BoNT/E12 – GenBank Accession No. KM370319.1) MLYMPKINSFNYNDPVNDRTILYIKPGGCQQFYKSFNIMKNIWIIPERNVIGTIPQDFQP PTSLKNGDSSYYDPN YLQSNEEKDRFLKIVTKIFNRINDNLSGGILLEELSKANPYLGNDNTPDGDFIINDASAV PIQFSNGSQSILLPN VIIMGAEPDLFETNSSNISLINNYRPSNHGFGSIAIVTFSPEYSFRFNDNSMNEFIQDPA LTLMHELIHSLHGLY GAKGITTKYTITQQQNSLITNIRGINIEEFLTFGGNDLNIITSSQFNDIYTNLLDDYKKI ASKLSQVRVSNPQLN PYKDVFQEKYGLDKDASGIYSVNINKFNDIFKKLYSFTEFDLATKFQVKCRETYIGQYKY FQLSNLLNDSIYNIS EGYNINNLKVNFRGQNANLNPRIITPITGRGLVKKIIRFCKNIVSVKGIRKSICIEVNNG ELFFVASENSYNDDN INTPKEIDDTVTSNNNYENDLDQVILNFNSESAPGLSDEKLNLTIQDDAYIPKYDSNGTS DIEQHDVNELNVFFY LDAQKVPEGENNVNLTSSIDTALLEQPKIYTFFSSEFINNVNKPVQAVLFVSWIQQVLVD FTTEATQKSTVDKIA DISIVVPYIGLALNIGNEAQKGNFKDALELLGAGILLEFVPELLIPTILVFTIKSFLGSS DNKNKIIKAINNALK ERDEKWKEVYSFIVSNWITKINTQFNKRKEQMYQALQNQVNAIKTIIESKYNSYTLEEKN ELTNKYDIKQIENEL NQKVSIAMNNIDRFLTESSISYLMKLINEVKINKLREYDENVKTYLLNYIIQHGSTLGES QQELNSMVINTLNNS IPFKLSSYTDDKILISYFNKFFKRIKSSSVLNMRYKNDKYVDTSGYDSNININGEIFIYP TNKNQFSIFNSKPSE VNISQNDYIIYDNKYKNFSISFWVRIPNYDNKIVNVNNEYTIINCMRDNNSGWKVSLNHN EIIWTLQDNAGINQK LAFNYGNSNGISDYINKWIFVTITNDRLGDSKLYINGNLIDQKSILNLGNIHVSDNILFK IVNCSYTRYIGIRYF NIFDKELDETEIQTLYSNEPNTNILKDFWGNYLLYDKEYYLLNVLKPNSIISHRRDLTFS FYNHRYIVNGLYRLY SGIKVKIQRVNDSSTNDQFVRKNDQVYINYIYNNLSYSLYADTNIKDKEKTIKSSLSGNI FNQVVVMNSVGNNCT MNFKNNNGNNIGLLGFKDNTLVASTWYYTHMRDNTNSNGCFWNFISEEHGWQEK The endogenous activation loop is dash-underlined. SEQ ID NO: 124 (BoNT/F1 - UniProt A7GBG3) MPVVINSFNYNDPVNDDTILYMQIPYEEKSKKYYKAFEIMRNVWIIPERNTIGTDPSDFD PPASLENGSSAYYDPNYLTTDAEKDRYLKTTIKLFKRINSNPAGEVLLQEISYAKPYLGN EHTPINEFHPVTRTTSVNIKSSTNVKSSIILNLLVLGAGPDIFENSSYPVRKLMDSGGVY DPSNDGFGSINIVTFSPEYEYTFNDISGGYNSSTESFIADPAISLAHELIHALHGLYGAR GVTYKETIKVKQAPLMIAEKPIRLEEFLTFGGQDLNIITSAMKEKIYNNLLANYEKIATR LSRVNSAPPEYDINEYKDYFQWKYGLDKNADGSYTVNENKFNEIYKKLYSFTEIDLANKF KVKCRNTYFIKYGFLKVPNLLDDDIYTVSEGFNIGNLAVNNRGQNIKLNPKIIDSIPDKG LVEKIVKFCKSVIPRKGTKAPPRLCIRVNNRELFFVASESSYNENDINTPKEIDDTTNLN NNYRNNLDEVILDYNSETIPQISNQTLNTLVQDDSYVPRYDSNGTSEIEEHNVVDLNVFF YLHAQKVPEGETNISLTSSIDTALSEESQVYTFFSSEFINTINKPVHAALFISWINQVIR DFTTEATQKSTFDKIADISLVVPYVGLALNIGNEVQKENFKEAFELLGAGILLEFVPELL IPTILVFTIKSFIGSSENKNKIIKAINNSLMERETKWKEIYSWIVSNWLTRINTQFNKRK EQMYQALQNQVDAIKTVIEYKYNNYTSDERNRLESEYNINNIREELNKKVSLAMENIERF ITESSIFYLMKLINEAKVSKLREYDEGVKEYLLDYISEHRSILGNSVQELNDLVTSTLNN SIPFELSSYTNDKILILYFNKLYKKIKDNSILDMRYENNKFIDISGYGSNISINGDVYIY STNRNQFGIYSSKPSEVNIAQNNDIIYNGRYQNFSISFWVRIPKYFNKVNLNNEYTIIDC IRNNNSGWKISLNYNKIIWTLQDTAGNNQKLVFNYTQMISISDYINKWIFVTITNNRLGN SRIYINGNLIDEKSISNLGDIHVSDNILFKIVGCNDTRYVGIRYFKVFDTELGKTEIETL YSDEPDPSILKDFWGNYLLYNKRYYLLNLLRTDKSITQNSNFLNINQQRGVYQKPNIFSN TRLYTGVEVIIRKNGSTDISNTDNFVRKNDLAYINVVDRDVEYRLYADISIAKPEKIIKL IRTSNSNNSLGQIIVMDSIGNNCTMNFQNNNGGNIGLLGFHSNNLVASSWYYNNIRKNTS SNGCFWSFISKEHGWQEN The endogenous activation loop is dash-underlined. SEQ ID NO: 125 (BoNT/F2 – GenBank Accession No. GU213209.1) MPVVINSFNYNDPVNDETILYMQKPYEERSRKYYKAFEIMPNVWIMPERDTIGTKPDEFQ VPDSLKNGSSAYYDP NYLTTDAEKDRYLKTMIKLFNRINSNPTGKVLLEEVSNARPYLGDDDTLINEFFPVNVTT SVNIKFSTDVESSII SNLLVLGAGPDIFKAYCTPLVRFNKSDKLIEPSNHGFGSINILTFSPEYEHIFNDISGGN HNSTESFIADPAISL AHELIHALHGLYGAKAVTHKESLVAERGPLMIAEKPIRLEEFLTFGGEDLNIIPSAMKEK IYNDLLANYEKIATR LREVNTAPPGYDINEYKDYFQWKYGLDRNADGSYTVNRNKFNEIYKKLYSFTEIDLANKF KVKCRNTYFIKYGFV KVPDLLDDDIYTVSEGFNIGNLAVNNRGQNINLNPKIIDSIPDKGLVEKIIKFCKSIIPR KGTKQSPSLCIRVNN RELFFVASESSYNESDINTPKEIDDTTNLNNNYRNNLDEVILDYNSETIPQISNRTLNTL VQDNSYVPRYDSNGT SEIEEYDVVDFNVFFYLHAQKVPEGETNISLTSSIDTALLEESKVYTFFSSEFIDTINKP VNAALFIDWISKVIR DFTTEATQKSTVDKIADISLIVPYVGLALNIVIEAEKGNFEEAFELLGAGILLEFVPELT IPVILVFTIKSYIDS YENKNKAIKAINNSLIEREAKWKEIYSWIVSNWLTRINTQFNKRKEQMYQALQNQVDAIK TAIEYKYNNYTSDEK NRLESKYNINNIEEELNKKVSLAMKNIERFMTESSISYLMKLINEAEVGKLKEYDKHVKS DLLDYILYHKLILGE QTKELIDLVTSTLNSSIPFELSSYTNDKILIIYFNRLYKKIKDSSILDMRYENNKFIDIS GYGSNISINGNVYIY STNRNQFGIYSGRLSEVNIAQNNDIIYNSRYQNFSISFWVRIPKHYRPMNRNREYTIINC MGNNNSGWKISLRTI RDCEIIWTLQDTSGNKEKLIFRYEELASISDYINKWIFVTITNNRLGNSRIYINGNLIVE KSISNLGDIHVSDNI LFKIVGCDDETYVGIRYFKVFNTELDKTEIETLYSNEPDPSILKDYWGNYLLYNKKYYLF NLLRKDKYITRNSGI LNINQQRGVTGGISVFLNYKLYEGVEVIIRKNAPIDISNTDNFVRKNDLAYINVVDHGVE YRLYADISITKSEKI IKLIRTSNPNDSLGQIIVMDSIGNNCTMNFQNNDGSNIGLLGFHSDDLVASSWYYNHIRR NTSSNGCFWSFISKE HGWKE The endogenous activation loop is dash-underlined. SEQ ID NO: 126 (BoNT/F3 – GenBank Accession No. GU213227.1) MPVVINSFNYNDPVNDETILYMQKPYEERSRKYYKAFEIMPNVWIMPERDTIGTKPDDFQ VPDSLKNGSSAYYDP NYLTTDAEKDRYLKTMIKLFNRINSNPTGKVLLEEVSNARPYLGDDDTLINEFFPVNVTT SVNIKFSTDVESSII SNLLVLGAGPDIFKAYCTPLVRFNKSDKLIEPSNHGFGSINILTFSPEYEHIFNDISGGD HNSTESFIADPAISL AHELIHALHGLYGAKAVTHKETIEVKRGPLMIAEKPIRLEEFLTFGGEDLNIIPSAMKEK IYNDLLANYEKIATR LREVNTAPPEYDINEYKDYFQWKYGLDRNADGSYTVNRNKFNGIYKKLYSFTEIDLANKF KVKCRNTYFIKYGFV KVPDLLDDDIYTVSEGFNIGNLAVNNRGQNINLNPKIIDSIPDKGLVEKIIKFCKSIIPR KGTKQSPSLCIRVNN RELFFVASESSYNESDINTPKEIDDTTNLNNNYRNNLDEVILDYNSETIPQISNRTLNTL VQDNSYVPRYDSNGT SEIEEYDVVDFNVFFYLHAQKVPEGETNISLTSSIDTALLEKSKVYTFFSSEFIDTINES VNAALFIDWINKVIR DFTTEATQKSTVDKIADISLIVPYVGLALNIVIDAEKGNFQEAFELLGAGILLEFVPELT IPVILVFTIKSYIDS YENKNKAIKAINNALIEREAKWKEIYSWIVSNWLTKINTQFNKRKEQMYQALQNQVDAIK TAIEYKYNNYTSDEK NRLESEYNINNIEEELNKKVSLAMKNIERFMTESSISYLMKLINEAEVGKLKKYDRHVKS DLLDYILYHKLILGD QTKELIDLVTSTLNSSIPFELSSYTNDKILIIYFNRLYKKIKDSSILDMRYENNKFIDIS GYGSNISINGNVYIY STNRNQFGIYSDRLSEVNIAQNNDIIYNSRYQNFSISFWVRIPKHYGPMNRNREYTIINC MGNNNSGWKISLRNI RDCEIIWTLQDTSGNKEKLIFRYEELANISDYINKWIFVTITNNRLGNSRIYINGNLIVE KSISNLGDIHVSDNI LFKIVGCDDKTYVGIRYFKVFNTELDKTEIETLYSNEPDPSILKDYWGNYLLYNKKYYLF NLLRKDKYITRNSGI LNINQQRGVTEGSVFLNYKLYEGVEVIIRKNGPIDISNTDNFVRKNDLAYINVVYHDVEY RLYADISITKPEKII KLIRTSNPNDSLGQIIVMDSIGNNCTMNFQNNNGGNIGLLGFHSDNLVASSWYYNNIRRN TSSNGCFWSFISKEH GWQE The endogenous activation loop is dash-underlined. SEQ ID NO: 127 (BoNT/F4 – GenBank Accession No. GU213214.1) MPVVINSFNYDDPVNDDTILYMQIPYEEKSKKYYKAFEIMRNVWIMPERNTIGTNPSDFD PPASLKNGSSAYYDP NYLTTDAEKDRYLKTTIKLFKRINSNPAGEVLLQEISYAKPYLGNDHTPINEFHPVTRTT SVNIKSSTNVESSII LNLLVLGAGPNIFENSSYPVRKLMNSGEVYDPSNDGFGSINIVTFSPEYEYTFNDISGGH NSSTESFIADPAISL AHELIHALHGLYGARGVTYKETIKVKQAPLMIAEKPIRLEEFLTFGGQDLNIITSAMKEK IYNDLLANYEKIATR LSEVNSAPPEYDINEYKNYFQWKYGLDKNADGSYTVNENKFNEIYKKLYSFTEIDLANKF KVKCRNTYFIKYGFL KVPNLLDDDIYTVSEGFNIGNLAVNNRGQNINLNPKIIDSIPDKGLVEKIVKLCKSIIPR KGTKAPPRLCIRVNN RELFFVASESSYNENDINTPKEIDDTTNLNNNYRNNLDEVILDYNSETIPQISSQTLNTL VQDDSYVPRYDSNGT SEIEEHNVVDLNAFFYLHAQKVPEGETNISLTSSIDTALSEESKVYTFFSSEFINNINKP VHAALFIGWISQVIR DFTTESTQKSTVDKIADISLIVPYVGLALNIGNDARKGNFKEAFELLGAAILLEVVPELL IPVILVFTIKSFIDS SKNEDKIIKAINNSLIEREAKWKEVYSWIVSNWLTRINTQFNKRKEQMYQALQNQVDAIK TVIEYKYNSYTSDEK NRLESEYNINNIEEELNKKVSLAMKNIERFIAESSISYLMKLINEAKVSELREYDEGVKE YLLDYILKNGSILGD HVQELNDLVTSTLNSSIPFELSSYTNDKILIIYFNKLYKKIKDNCILDMRYENNKFIDIS GYGSNISINGELYIY TTNRNQFTIYSGKLSEVNIAQNNDIIYNSRYQNFSISFWVRIPRYSNIVNLNNEYTIINC MGNNNSGWKISLNYN KIIWTLQDTAGNNEKLVFNYTQMISISDYINKWIFVTITNNRLGNSRIYINGNLIDQKSI SNLGDIHVSDNILFK IVGCNDTRYVGIRYFKVFDTELDKTEIETLYSDEPDPSILKDFWGNYLLYNKRYYLLNLL RKDNAITQSSTFLSI SRARGVDRKANIFSNKRLYKGVEVIIRKNEPIDISNTDNFVRKGDLAYINVVDRDVEYRL YANTSNAQPEKTIKL IRTSNSNDSLDQIIVMDSIGNNCTMNFQNNNGGNIGLLGFHSNTLVASSWYYNNIRRNTS SNGCFWSFISKEHGW QE The endogenous activation loop is dash-underlined. SEQ ID NO: 128 (BoNT/F5 – GenBank Accession No. GU213211.1) MPVEINSFNYDDLVNDNTILYIRPPYYERSNTYFKAFNIMENVWIIPERYRLGIEASKFD PPDSLKAGSDGYFDP NYLSTNTEKNRYLQIMIKLFKRINSNEAGKILLNQIKDAIPYLGNSYTAEDQFTTNNRTI SFNVRLANGTIEQEM ANLIIWGPGPDLTTNRTGGTTYTPAQSLEAIPYKEGFGSIMTIEFSPEYATAFNDISLTS HAPSLFIKDPALILM HELIHVLHGLYGTYTTGFKIKPNITEPYMEVTKPITSGEFLTFGGNDVNKIPQLIQSQLR SKVLDDYEKIASRLN KVNRATAEINIDKFKYSYQLKYQFVKDSNGVYSVDLDKFNKLYDKIYSFTEFNLAHEFKI KTRNSYLAKNFGPFY LPNLLDNSIYNEADGFNIGDLSVNYKGQVIGSDIDSIKKLEGQGVVSRVVRLCLNSSFKK NTKKPLCITVNNGDL FFIASEDSYGEDTINTPKEIDDTTTLVPSFKNILDKVILDFNKQVTPQIPNRRIRTDIQE DNYIPEYDSNGTSEI EEYNVVDLNAFFYLHAQKVPEGETNISLTSSIDTALSEESKVYTFFSSEFIDTINEPVNA ALFIDWISKVIRDFT TEATQKSTVDKIADISLIVPYVGLALNIVNETEKGNFKEAFELLGAGILLEFVPELAIPV ILVFTIKSYIDSYEN KNKIIKAINNSLIEREAKWKEIYSWIVSNWLTRINTQFNKRKEQMYQALQNQVDAIKTAI EYKYNNYTSDEKNRL ESEYNINNIEEELNKKVSLAMKNIERFITESSISYLMKLINEAEVGKLKEYDKRVKRHLL EYIFDYRLILGEQGG ELIDLVTSTLNTSIPFELSSYTNDKILIIYFNRLYKKIKDSSILDMRYENNKFIDISGYG SNISINGNVYIYSTN RNQFGIYDDRLSEVNIAQNNDIIYNSRYQNFSISFWVRIPKHYRPMNHNREYTIINCMGN NNSGWKISLRTTGDC EIIWTLQDTSGNKKKLIFRYSQLGGISDYINKWIFVTITNNRLGNSRIYINGNLIVEKSI SNLGDIHVSDNILFK IVGCDDKMYVGIRYFKVFNTELDKTEIEILYSNEPDPSILKDYWGNYLLYNKKYYLLNLL RNDKYITRNSDILNI SHQRGVTKDLFIFSNYKLYEGVEVIIRKNGPIDISNTDNFVRKNDLAYINVVDHGVEYRL YADISITKPEKIIKL IRRSNPDDSLGQIIVMDSIGNNCTMNFQNNNGGNIGLLGFHSDNLVASSWYYNNIRRNTS SNGCFWSFISKEHGW QE The endogenous activation loop is dash-underlined. SEQ ID NO: 129 (BoNT/F6 – GenBank Accession No. M92906.1) MPVAINSFNYNDPVNDDTILYMQIPYEEKSKKYYKAFEIMRNVWIIPERNTIGTNPSDFD PPASLKNGSSAYYDP NYLTTDAEKDRYLKTTIKLFKRINSNPAGKVLLQEISYAKPYLGNDHTPIDEFSPVTRTT SVNIKLSTNVESSML LNLLVLGAGPDIFESCCYPVRKLIDPDVVYDPSNYGFGSINIVTFSPEYEYTFNDISGGH NSSTESFIADPAISL AHELIHALHGLYGARGVTYEETIEVKQAPLMIAEKPIRLEEFLTFGGQDLNIITSAMKEK IYNNLLANYEKIATR LSEVNSAPPEYDINEYKDYFQWKYGLDKNADGSYTVNENKFNEIYKKLYSFTESDLANKF KVKCRNTYFIKYEFL KVPNLLDDDIYTVSEGFNIGNLAVNNRGQSIKLNPKIIDSIPDKGLVEKIVKFCKSVIPR KGTKAPPRLCIRVNN SELFFVASESSYNENDINTPKEIDDTTNLNNNYRNNLDEVILDYNSQTIPQISNRTLNTL VQDNSYVPRYDSNGT SEIEEYDVVDFNVFFYLHAQKVPEGETNISLTSSIDTALLEESKDIFFSSEFIDTINKPV NAALFIDWISKVIRD FTTEATQKSTVDKIADISLIVPYVGLALNIIIEAEKGNFEEAFELLGVGILLEFVPELTI PVILVFTIKSYIDSY ENKNKAIKAINNSLIEREAKWKEIYSWIVSNWLTRINTQFNKRKEQMYQALQNQVDAIKT AIEYKYNNYTSDEKN RLESEYNINNIEEELNKKVSLAMKNIERFMTESSISYLMKLINEAKVGKLKKYDNHVKSD LLNYILDHRSILGEQ TNELSDLVTSTLNSSIPFELSSYTNDKILIIYFNRLYKKIKDSSILDMRYENNKFIDISG YGSNISINGNVYIYS TNRNQFGIYNSRLSEVNIAQNNDIIYNSRYQNFSISFWVRIPKHYKPMNHNREYTIINCM GNNNSGWKISLRTVR DCEIIWTLQDTSGNKENLIFRYEELNRISNYINKWIFVTITNNRLGNSRIYINGNLIVEK SISNLGDIHVSDNIL FKIVGCDDETYVGIRYFKVFNTELDKTEIETLYSNEPDPSILKNYWGNYLLYNKKYYLFN LLRKDKYITLNSGIL NINQQRGVTEGSVFLNYKLYEGVEVIIRKNGPIDISNTDNFVRKNDLAYINVVDRGVEYR LYADTKSEKEKIIRT SNLNDSLGQIIVMDSIGNNCTMNFQNNNGSNIGLLGFHSNNLVASSWYYNNIRRNTSSNG CFWSSISKENGWKE The endogenous activation loop is dash-underlined. SEQ ID NO: 130 (BoNT/F7 – GenBank Accession No. GU213233.1) MPVNINNFNYNDPINNTTILYMKMPYYEDSNKYYKAFEIMDNVWIIPERNIIGKKPSDFY PPISLDSGSSAYYDP NYLTTDAEKDRFLKTVIKLFNRINSNPAGQVLLEEIKNGKPYLGNDHTAVNEFCANNRST SVEIKESNGTTDSML LNLVILGPGPNILECSTFPVRIFPNNIAYDPSEKGFGSIQLMSFSTEYEYAFNDNTDLFI ADPAISLAHELIHVL HGLYGAKGVTNKKVIEVDQGALMAAEKDIKIEEFITFGGQDLNIITNSTNQKIYDNLLSN YTAIASRLSQVNINN SALNTTYYKNFFQWKYGLDQDSNGNYTVNISKFNAIYKKLFSFTECDLAQKFQVKNRSNY LFHFKPFRLLDLLDD NIYSISEGFNIGSLRVNNNGQNINLNSRIVGPIPDNGLVERFVGLCKSIVSKKGTKNSLC IKVNNRDLFFVASES SYNENGINSPKEIDDTTITNNNYKKNLDEVILDYNSDAIPNLSSRLLNTTAQNDSYVPKY DSNGTSEIKEYTVDK LNVFFYLYAQKAPEGESAISLTSSVNTALLDASKVYTFFSSDFINTVNKPVQAALFISWI QQVINDFTTEATQKS TIDKIADISLVVPYVGLALNIGNEVQKGNFKEAIELLGAGILLEFVPELLIPTILVFTIK SFINSDDSKNKIIKA INNALRERELKWKEVYSWIVSNWLTRINTQFNKRKEQMYQALQNQVDGIKKIIEYKYNNY TLDEKNRLKAEYNIY SIKEELNKKVSLAMQNIDRFLTESSISYLMKLINEAKINKLSEYDKRVNQYLLNYILENS STLGTSSVQELNNLV SNTLNNSIPFELSEYTNDKILISYFNRFYKRIIDSSILNMKYENNRFIDSSGYGSNISIN GDIYIYSTNRNQFGI YSSRLSEVNITQNNTIIYNSRYQNFSVSFWVRIPKYNNLKNLNNEYTIINCMRNNNSGWK ISLNYNNIIWTLQDT TGNNQKLVFNYTQMIDISDYINKWTFVTITNNRLGHSKLYINGNLTDQKSILNLGNIHVD DNILFKIVGCNDTRY VGIRYFKIFNMELDKTEIETLYHSEPDSTILKDFWGNYLLYNKKYYLLNLLKPNMSVTKN SDILNINRQRGIYSK TNIFSNARLYTGVEVIIRKVGSTDTSNTDNFVRKNDTVYINVVDGNSEYQLYADVSTSAV EKTIKLRRISNSNYN SNQMIIMDSIGDNCTMNFKTNNGNDIGLLGFHLNNLVASSWYYKNIRNNTRNNGCFWSFI SKEHGWQE The endogenous activation loop is dash-underlined. SEQ ID NO: 131 (BoNT/G - UniProt Q60393) MPVNIKXFNYNDPINNDDIIMMEPFNDPGPGTYYKAFRIIDRIWIVPERFTYGFQPDQFN ASTGVFSKDVYEYYDPTYLKTDAEKDKFLKTMIKLFNRINSKPSGQRLLDMIVDAIPYLG NASTPPDKFAANVANVSINKKIIQPGAEDQIKGLMTNLIIFGPGPVLSDNFTDSMIMNGH SPISEGFGARMMIRFCPSCLNVFNNVQENKDTSIFSRRAYFADPALTLMHELIHVLHGLY GIKISNLPITPNTKEFFMQHSDPVQAEELYTFGGHDPSVISPSTDMNIYNKALQNFQDIA NRLNIVSSAQGSGIDISLYKQIYKNKYDFVEDPNGKYSVDKDKFDKLYKALMFGFTETNL AGEYGIKTRYSYFSEYLPPIKTEKLLDNTIYTQNEGFNIASKNLKTEFNGQNKAVNKEAY EEISLEHLVIYRIAMCKPVMYKNTGKSEQCIIVNNEDLFFIANKDSFSKDLAKAETIAYN TQNNTIENNFSIDQLILDNDLSSGIDLPNENTEPFTNFDDIDIPVYIKQSALKKIFVDGD SLFEYLHAQTFPSNIENLQLTNSLNDALRNNNKVYTFFSTNLVEKANTVVGASLFVNWVK GVIDDFTSESTQKSTIDKVSDVSIIIPYIGPALNVGNETAKENFKNAFEIGGAAILMEFI PELIVPIVGFFTLESYVGNKGHIIMTISNALKKRDQKWTDMYGLIVSQWLSTVNTQFYTI KERMYNALNNQSQAIEKIIEDQYNRYSEEDKMNINIDFNDIDFKLNQSINLAINNIDDFI NQCSISYLMNRMIPLAVKKLKDFDDNLKRDLLEYIDTNELYLLDEVNILKSKVNRHLKDS IPFDLSLYTKDTILIQVFNNYISNISSNAILSLSYRGGRLIDSSGYGATMNVGSDVIFND IGNGQFKLNNSENSNITAHQSKFVVYDSMFDNFSINFWVRTPKYNNNDIQTYLQNEYTII SCIKNDSGWKVSIKGNRIIWTLIDVNAKSKSIFFEYSIKDNISDYINKWFSITITNDRLG NANIYINGSLKKSEKILNLDRINSSNDIDFKLINCTDTTKFVWIKDFNIFGRELNATEVS SLYWIQSSTNTLKDFWGNPLRYDTQYYLFNQGMQNIYIKYFSKASMGETAPRTNFNNAAI NYQNLYLGLRFIIKKASNSRNINNDNIVREGDYIYLNIDNISDESYRVYVLVNSKEIQTQ LFLAPINDDPTFYDVLQIKKYYEKTTYNCQILCEKDTKTFGLFGIGKFVKDYGYVWDTYD NYFCISQWYLRRISENINKLRLGCNWQFIPVDEGWTE The endogenous activation loop is dash-underlined. SEQ ID NO: 132 (BoNT/FA – GenBank Accession No. KGO15617.1) MPVVINSFNYDDPVNDNTIIYIRPPYYETSNTYFKAFQIMDNVWIIPERYRLGIDPSLFN PPVSLKAGSDGYFDP NYLSTNTEKNKYLQIMIKLFKRINSKPAGQILLEEIKNAIPYLGNSYTQEEQFTTNNRTV SFNVKLANGNIVQQM ANLIIWGPGPDLTTNKTGGIIYSPYQSMEATPYKDGFGSIMTVEFSPEYATAFNDISIAS HSPSLFIKDPALILM HELIHVLHGLYGTYITEYKITPNVVQSYMKVTKPITSAEFLTFGGRDRNIVPQSIQSQLY NKVLSDYKRIASRLN KVNTATALINIDEFKNLYEWKYQFAKDSNGVYSVDLNKFEQLYKKIYSFTEFNLAYEFKI KTRLGYLAENFGPFY LPNLLDDSIYTEVDGFNIGALSINYQGQNIGSDINSIKKLQGQGVVSRVVRLCSNSNTKN SLCITVNNRDLFFIA SQESYGENTINTYKEIDDTTTLDPSFEDILDKVILNFNEQVIPQMPNRNVSTDIQKDNYI PKYDYNRTDIIDSYE VGRNYNTFFYLNAQKFSPNESNITLTSSFDTGLLEGSKVYTFFSSDFINNINKPVQALLF IEWVKQVIRDFTTEA TKTSTVDKLKDISLVVPYIGLALNIGDEIYKQHFAEAVELVGAGLLLEFSPEFLIPTLLI FTIKGYLTGSIRDKD KIIKTLDNALNVRDQKWKELYRWVVSKWLTTINTQFNKRKEQMYKALKNQATAIKKIIEN KYNNYTTDEKSKIDS SYNINEIERTLNEKINLAMKNIEQFITESSIAYLINIINNETIQKLKSYDDLVRRYLLGY IRNHSSILGNSVEEL NSKVNNHLDNGIPFELSSYTNDSLLIRYFNKNYGELKYNCILNIKYEMDRDKLVDSSGYR SRINIGTGVKFSEID KNQVQLSNLESSKIEVILNNGVIYNSMYENFSTSFWIRIPKYFRNINNEYKIISCMQNNS GWEVSLNFSNMNSKI IWTLQDTEGIKKTVVFQYTQNINISDYINRWIFVTITNNRLSNSKIYINGRLINEESISD LGNIHASNNIMFKLD GCRDPHRYIWIKYFNLFDKELNKKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYD PNKYLDVNNVGIRGY MYLKGPRGRIVTTNIYLNSTLYMGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRL ATNASQAGVEKILSA VEIPDVGNLSQVVVMKSENDQGIRNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYN RQIGKASRTFGCSWE FIPVDDGWGESSL The endogenous activation loop is dash-underlined. SEQ ID NO: 133 (Polypeptide Sequence of BoNT/X) MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADAIYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIP LPLVSNGALTLSDNETIAYQENNNIVSNLQANLVIYGPGPDIANNATYGLYSTPISNGEG TLSEVSFSPFYLKPFDESYGNYRSLVNIVNKFVKREFAPDPASTLMHELVHVTHNLYGIS NRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKKIIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVNILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFI KICPRNGLLYNAIYRNSKNYLNNIDLEDKKTTSKTNVSYPCSLLNGCIEVENKDLFLISN KDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSISQQNILERNEELY EPIRNSLFEIKTIYVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPF KNMSNTINSIETGITSTYIFYQWLRSIVKDFSDETGKIDVIDKSSDTLAIVPYIGPLLNI GNDIRHGDFVGAIELAGITALLEYVPEFTIPILVGLEVIGGELAREQVEAIVNNALDKRD QKWAEVYNITKAQWWGTIHLQINTRLAHTYKALSRQANAIKMNMEFQLANYKGNIDDKAK IKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETKKTLDK FIKEKEDILGTNLSSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNEIEDYEVLNL GAEDGKIKDLSGTTSDINIGSDIELADGRENKAIKIKGSENSTIKIAMNKYLRFSATDNF SISFWIKHPKPTNLLNNGIEYTLVENFNQRGWKISIQDSKLIWYLRDHNNSIKIVTPDYI AFNGWNLITITNNRSKGSIVYVNGSKIEEKDISSIWNTEVDDPIIFRLKNNRDTQAFTLL DQFSIYRKELNQNEVVKLYNYYFNSNYIRDIWGNPLQYNKKYYLQTQDKPGKGLIREYWS SFGYDYVILSDSKTITFPNNIRYGALYNGSKVLIKNSKKLDGLVRNKDFIQLEIDGYNMG ISADRFNEDTNYIGTTYGTTHDLTTDFEIIQRQEKYRNYCQLKTPYNIFHKSGLMSTETS KPTFHDYRDWVYSSAWYFQNYENLNLRKHTKTNWYFIPKDEGWDED The endogenous activation loop is dash-underlined. SEQ ID NO: 134 (TeNT – UniProt P04958) MPITINNFRYSDPVNNDTIIMMEPPYCKGLDIYYKAFKITDRIWIVPERYEFGTKPEDFN PPSSLIEGASEYYDPNYLRTDSDKDRFLQTMVKLFNRIKNNVAGEALLDKIINAIPYLGN SYSLLDKFDTNSNSVSFNLLEQDPSGATTKSAMLTNLIIFGPGPVLNKNEVRGIVLRVDN KNYFPCRDGFGSIMQMAFCPEYVPTFDNVIENITSLTIGKSKYFQDPALLLMHELIHVLH GLYGMQVSSHEIIPSKQEIYMQHTYPISAEELFTFGGQDANLISIDIKNDLYEKTLNDYK AIANKLSQVTSCNDPNIDIDSYKQIYQQKYQFDKDSNGQYIVNEDKFQILYNSIMYGFTE IELGKKFNIKTRLSYFSMNHDPVKIPNLLDDTIYNDTEGFNIESKDLKSEYKGQNMRVNT NAFRNVDGSGLVSKLIGLCKKIIPPTNIRENLYNRTASLTDLGGELCIKIKNEDLTFIAE KNSFSEEPFQDEIVSYNTKNKPLNFNYSLDKIIVDYNLQSKITLPNDRTTPVTKGIPYAP EYKSNAASTIEIHNIDDNTIYQYLYAQKSPTTLQRITMTNSVDDALINSTKIYSYFPSVI SKVNQGAQGILFLQWVRDIIDDFTNESSQKTTIDKISDVSTIVPYIGPALNIVKQGYEGN FIGALETTGVVLLLEYIPEITLPVIAALSIAESSTQKEKIIKTIDNFLEKRYEKWIEVYK LVKAKWLGTVNTQFQKRSYQMYRSLEYQVDAIKKIIDYEYKIYSGPDKEQIADEINNLKN KLEEKANKAMININIFMRESSRSFLVNQMINEAKKQLLEFDTQSKNILMQYIKANSKFIG ITELKKLESKINKVFSTPIPFSYSKNLDCWVDNEEDIDVILKKSTILNLDINNDIISDIS GFNSSVITYPDAQLVPGINGKAIHLVNNESSEVIVHKAMDIEYNDMFNNFTVSFWLRVPK VSASHLEQYGTNEYSIISSMKKHSLSIGSGWSVSLKGNNLIWTLKDSAGEVRQITFRDLP DKFNAYLANKWVFITITNDRLSSANLYINGVLMGSAEITGLGAIREDNNITLKLDRCNNN NQYVSIDKFRIFCKALNPKEIEKLYTSYLSITFLRDFWGNPLRYDTEYYLIPVASSSKDV QLKNITDYMYLTNAPSYTNGKLNIYYRRLYNGLKFIIKRYTPNNEIDSFVKSGDFIKLYV SYNNNEHIVGYPKDGNAFNNLDRILRVGYNAPGIPLYKKMEAVKLRDLKTYSVQLKLYDD KNASLGLVGTHNGQIGNDPNRDILIASNWYFNHLKDKILGCDWYFVPTDEGWTND The endogenous activation loop is dash-underlined. SEQ ID NO: 135 (BoNT/A GenBank Accession No. AF488749.1) MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGG STIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGY GSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPN RVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFT GLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEE ITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNG KKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEA AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG AVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAK VNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKA MININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDK VNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINI GSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNN EYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTIT NNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELN EKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPR GSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQA GVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAK LVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL The endogenous activation loop is dash-underlined. SEQ ID NO: 136 non-engineered BoNT/AB chimera MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGII TSKTKSLDKGYNKAL NDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDN EPENISIENLSSDII GQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTF FSSDYVKKVNKATEA AMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSG AVILLEFIPEIAIPV LGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEA LENQAEATKAIINYQ YNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLED FDASLKDALLKYIYD NRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNILNNIILNLRYKD NNLIDLSGYGAKVEV YDGVELNDKNQFKLTSSANSKIRVTQNQNIIFNSVFLDFSVSFWIRIPKYKNDGIQNYIH NEYTIINCMKNNSGW KISIRGNRIIWTLIDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLNNAKIYINGKL ESNTDIKDIREVIAN GEIIFKLDGDIDRTQFIWMKYFSIFNTELSQSNIEERYKIQSYSEYLKDFWGNPLMYNKE YYMFNAGNKNSYIKL KKDSPVGEILTRSKYNQNSKYINYRDLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFF NLNQEWRVYTYKYFK KEEMKLFLAPIYDSDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESG IVFEEYKDYFCISKW YLKEVKRKPYNLKLGCNWQFIPKDEGWTE SytII-binding mutations E1191M and S1199Y are bold and underlined. The endogenous activation loop is dash-underlined. SEQ ID NO: 137 GS linker consensus (GGGGS)n SEQ ID NO: 138 GS5 linker GGGGS SEQ ID NO: 139 GS10 linker GGGGSGGGGS SEQ ID NO: 140 GS15 linker GGGGSGGGGSGGGGS SEQ ID NO: 141 GS20 linker GGGGSGGGGSGGGGSGGGGS SEQ ID NO: 142 GS25 linker GGGGSGGGGSGGGGSGGGGSGGGGS SEQ ID NO: 143 metal coordinating SNARE cleavage motif HEXXH SEQ ID NO: 144 leucine-based motif xDxxxLL SEQ ID NO: 145 leucine-based motif xExxxLL SEQ ID NO: 146 leucine-based motif xExxxIL SEQ ID NO: 147 leucine-based motif xExxxLM SEQ ID NO: 148 TEV(Tobacco Etch virus) cleavage motif ENLYFQG SEQ ID NO: 149 PreScission cleavage motif LEVLFQGP SEQ ID NO: 150 LC/A1-Cloop-H _N /A1 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKAID GRSLYNKTLDCIKVN NWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIE NLSSDIIGQLELMPN IERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKK VNKATEAAMFLGWVE QLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFI PEIAIPVLGTFALVS YIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEAT KAIINYQYNQYTEEE KNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDA LLKYIYDNRGTLIGQ VDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKN LC/A1 is italicised BoNT/C activation loop is bold and underlined H _N A1 is C-terminal to the C activation loop and is neither underlined nor italicised SEQ ID NO: 151 LC/A1- Exogenous Activation Loop -HN/A1 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLL [EXOGENOUS PROTEASE CLEAVAGE SITE AS DEFINED HEREIN] IKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPEN ISIENLSSDIIGQLE LMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSD YVKKVNKATEAAMFL GWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVIL LEFIPEIAIPVLGTF ALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQ AEATKAIINYQYNQY TEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDAS LKDALLKYIYDNRGT LIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKN LC/A1 is italicised Exogenous activation loop is bold and underlined HNA1 is C-terminal to the C activation loop and is neither underlined nor italicised SEQ ID NO: 152: LC/X-Cloop-HN/X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICHKAIDGRSLYNK TLDCIEVENKDLFLI SNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSISQQNILERNEE LYEPIRNSLFEIKTI YVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKNMSNTINSIETG ITSTYIFYQWLRSIV KDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAGITALLEYVPEF TIPILVGLEVIGGEL AREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKALSRQANAIKMN MEFQLANYKGNIDDK AKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETKKTL DKFIKEKEDILGTNL SSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNE LC/X is italicised BoNT/C activation loop is bold and underlined HNX is C-terminal to the C activation loop and is neither underlined nor italicised SEQ ID NO: 153: LC/X-Exogenous Activation Loop-HN/X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKI[EXOGENOUS PROTEASE CLEAVAGE SITE AS DEFINED HEREIN] IEVENKDLFLISNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSI SQQNILERNEELYEP IRNSLFEIKTIYVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKN MSNTINSIETGITST YIFYQWLRSIVKDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAG ITALLEYVPEFTIPI LVGLEVIGGELAREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKA LSRQANAIKMNMEFQ LANYKGNIDDKAKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNL KNFDLETKKTLDKFI KEKEDILGTNLSSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNE LC/X is italicised Exogenous activation loop is bold and underlined HNX is C-terminal to the C activation loop and is neither underlined nor italicised SEQ ID NO: 154: Nucleic acid encoding exemplary engineered BoNT/A1B1 chimera with modified Cloop/ PPFGRSAG of SEQ ID NO: 63 ATGCCATTCGTCAACAAGCAATTCAACTACAAAGACCCAGTCAACGGCGTCGACATCGCA TACATCAAGATTCCG AACGCCGGTCAAATGCAGCCGGTTAAGGCTTTTAAGATCCACAACAAGATTTGGGTTATC CCGGAGCGTGACACC TTCACGAACCCGGAAGAAGGCGATCTGAACCCGCCACCGGAAGCGAAGCAAGTCCCTGTC AGCTACTACGATTCG ACGTACCTGAGCACGGATAACGAAAAAGATAACTACCTGAAAGGTGTGACCAAGCTGTTC GAACGTATCTACAGC ACGGATCTGGGTCGCATGCTGCTGACTAGCATTGTTCGCGGTATCCCGTTCTGGGGTGGT AGCACGATTGACACC GAACTGAAGGTTATCGACACTAACTGCATTAACGTTATTCAACCGGATGGTAGCTATCGT AGCGAAGAGCTGAAT CTGGTCATCATTGGCCCGAGCGCAGACATTATCCAATTCGAGTGCAAGAGCTTTGGTCAC GAGGTTCTGAATCTG ACCCGCAATGGCTATGGTAGCACCCAGTACATTCGTTTTTCGCCGGATTTTACCTTCGGC TTTGAAGAGAGCCTG GAGGTTGATACCAATCCGTTGCTGGGTGCGGGCAAATTCGCTACCGATCCGGCTGTCACG CTGGCCCATGAACTG ATCCACGCAGGCCACCGCCTGTACGGCATTGCCATCAACCCAAACCGTGTGTTCAAGGTT AATACGAATGCATAC TACGAGATGAGCGGCCTGGAAGTCAGCTTCGAAGAACTGCGCACCTTCGGTGGCCATGAC GCTAAATTCATTGAC AGCTTGCAAGAGAATGAGTTCCGTCTGTACTACTATAACAAATTCAAAGACATTGCAAGC ACGTTGAACAAGGCC AAAAGCATCGTTGGTACTACCGCGTCGTTGCAGTATATGAAGAATGTGTTTAAAGAGAAG TACCTGCTGTCCGAG GATACCTCCGGCAAGTTTAGCGTTGATAAGCTGAAGTTTGACAAACTGTACAAGATGCTG ACCGAGATTTACACC GAGGACAACTTTGTGAAATTCTTCAAAGTGTTGAATCGTAAAACCTATCTGAATTTTGAC AAAGCGGTTTTCAAG ATTAACATCGTGCCGAAGGTGAACTACACCATCTATGACGGTTTTAACCTGCGTAACACC AACCTGGCGGCGAAC TTTAACGGTCAGAATACGGAAATCAACAACATGAATTTCACGAAGTTGAAGAACTTCACG GGTCTGTTCGAGTTC TATAAGCTGCTGTGTCATAAAGCCATTCCGCCGTTTGGTCGTAGCGCAGGTTATAACAAA ACCCTGGATTGTATT AAGGTAAACAATTGGGATCTGTTCTTTTCGCCATCCGAAGATAATTTTACCAACGACCTG AACAAGGGTGAAGAA ATCACCAGCGATACGAATATTGAAGCAGCGGAAGAGAATATCAGCCTGGATCTGATCCAG CAGTACTATCTGACC TTTAACTTCGACAATGAACCGGAGAACATTAGCATTGAGAATCTGAGCAGCGACATTATC GGTCAGCTGGAACTG ATGCCGAATATCGAACGTTTCCCGAACGGCAAAAAGTACGAGCTGGACAAGTACACTATG TTCCATTACCTGCGT GCACAGGAGTTTGAACACGGTAAAAGCCGTATCGCGCTGACCAACAGCGTTAACGAGGCC CTGCTGAACCCGAGC CGTGTCTATACCTTCTTCAGCAGCGACTATGTTAAGAAAGTGAACAAAGCCACTGAGGCC GCGATGTTCCTGGGC TGGGTGGAACAGCTGGTATATGACTTCACGGACGAGACGAGCGAAGTGAGCACTACCGAC AAAATTGCTGATATT ACCATCATTATCCCGTATATTGGTCCGGCACTGAACATTGGCAACATGCTGTACAAAGAC GATTTTGTGGGTGCC CTGATCTTCTCCGGTGCCGTGATTCTGCTGGAGTTCATTCCGGAGATTGCGATCCCGGTG TTGGGTACCTTCGCG CTGGTGTCCTACATCGCGAATAAGGTTCTGACGGTTCAGACCATCGATAACGCGCTGTCG AAACGTAATGAAAAA TGGGACGAGGTTTACAAATACATTGTTACGAATTGGCTGGCGAAAGTCAATACCCAGATC GACCTGATCCGTAAG AAAATGAAAGAGGCGCTGGAGAATCAGGCGGAGGCCACCAAAGCAATTATCAACTACCAA TACAACCAGTACACG GAAGAAGAGAAGAATAACATTAACTTCAATATCGATGATTTGAGCAGCAAGCTGAATGAA TCTATCAACAAAGCG ATGATCAATATCAACAAGTTTTTGAATCAGTGTAGCGTTTCGTACCTGATGAATAGCATG ATTCCGTATGGCGTC AAACGTCTGGAGGACTTCGACGCCAGCCTGAAAGATGCGTTGCTGAAATACATTTACGAC AATCGTGGTACGCTG ATTGGCCAAGTTGACCGCTTGAAAGACAAAGTTAACAATACCCTGAGCACCGACATCCCA TTTCAACTGAGCAAG TATGTTGATAATCAACGTCTGTTGAGCACTTTCACCGAGTATATCAAAAACATTCTGAAC AATATTATCCTGAAC CTGCGTTACAAAGACAACAATCTGATCGATCTGAGCGGCTATGGTGCAAAAGTTGAAGTC TACGACGGTGTCGAA CTGAACGATAAAAACCAGTTCAAACTGACCTCATCGGCTAACTCAAAAATTCGTGTGACG CAGAACCAAAACATC ATCTTCAACTCGGTCTTTCTGGACTTCAGCGTGTCTTTCTGGATTCGCATCCCGAAATAT AAAAATGATGGCATC CAGAACTACATCCATAACGAATACACCATCATCAACTGTATGAAAAACAACAGTGGTTGG AAAATTTCCATCCGT GGCAACCGCATTATCTGGACCCTGATTGATATCAATGGTAAAACGAAAAGCGTGTTTTTC GAATACAACATCCGT GAAGATATCTCTGAATACATCAATCGCTGGTTTTTCGTGACCATTACGAACAATCTGAAC AATGCGAAAATCTAT ATCAACGGCAAACTGGAAAGTAATACCGACATCAAAGATATTCGTGAAGTTATCGCCAAC GGTGAAATCATCTTC AAACTGGATGGCGACATCGATCGCACCCAGTTCATTTGGATGAAATACTTCTCCATCTTC AACACGGAACTGAGT CAGTCCAATATCGAAGAACGCTACAAAATCCAATCATACTCGGAATACCTGAAAGATTTC TGGGGTAACCCGCTG ATGTACAACAAAGAATACTACATGTTCAACGCGGGCAACAAAAACTCATACATCAAACTG AAAAAAGATTCGCCG GTGGGTGAAATCCTGACCCGTAGCAAATACAACCAGAACTCTAAATACATCAACTATCGC GATCTGTACATTGGC GAAAAATTTATTATCCGTCGCAAAAGCAACTCTCAGAGTATTAATGATGACATCGTGCGT AAAGAAGACTACATC TATCTGGATTTCTTTAATCTGAACCAAGAATGGCGCGTTTATACCTACAAATACTTCAAA AAAGAAGAAATGAAA CTGTTCCTGGCCCCGATTTACGACAGCGATGAATTTTACAACACCATCCAGATCAAAGAA TACGATGAACAGCCG ACGTATAGTTGCCAACTGCTGTTCAAAAAAGACGAAGAATCCACCGATGAAATTGGCCTG ATTGGTATCCACCGT TTCTATGAAAGCGGTATCGTTTTCGAAGAATACAAAGATTACTTCTGTATCTCTAAATGG TATCTGAAAGAAGTC AAACGCAAACCGTACAACCTGAAACTGGGCTGCAACTGGCAATTTATCCCGAAAGACGAA GGCTGGACCGAA SEQ ID NO: 155: Exemplary engineered BoNT/A1B1 chimera with modified Cloop/ PPFGRSAG of SEQ ID NO: 63 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKAIP PFGRSAGYNKTLDCI KVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENI SIENLSSDIIGQLEL MPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDY VKKVNKATEAAMFLG WVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILL EFIPEIAIPVLGTFA LVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQA EATKAIINYQYNQYT EEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASL KDALLKYIYDNRGTL IGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNILNNIILNLRYKDNNLID LSGYGAKVEVYDGVE LNDKNQFKLTSSANSKIRVTQNQNIIFNSVFLDFSVSFWIRIPKYKNDGIQNYIHNEYTI INCMKNNSGWKISIR GNRIIWTLIDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLNNAKIYINGKLESNTD IKDIREVIANGEIIF KLDGDIDRTQFIWMKYFSIFNTELSQSNIEERYKIQSYSEYLKDFWGNPLMYNKEYYMFN AGNKNSYIKLKKDSP VGEILTRSKYNQNSKYINYRDLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQE WRVYTYKYFKKEEMK LFLAPIYDSDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFEE YKDYFCISKWYLKEV KRKPYNLKLGCNWQFIPKDEGWTE LC/A1 is italicised Exogenous activation loop of SEQ ID NO: 63 is bold and underlined HNB1 is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 156: Nucleic acid encoding exemplary engineered BoNT/A1B1 chimera with modified Cloop/ SGRSA of SEQ ID NO: 65 ATGCCATTCGTCAACAAGCAATTCAACTACAAAGACCCAGTCAACGGCGTCGACATCGCA TACATCAAGATTCCG AACGCCGGTCAAATGCAGCCGGTTAAGGCTTTTAAGATCCACAACAAGATTTGGGTTATC CCGGAGCGTGACACC TTCACGAACCCGGAAGAAGGCGATCTGAACCCGCCACCGGAAGCGAAGCAAGTCCCTGTC AGCTACTACGATTCG ACGTACCTGAGCACGGATAACGAAAAAGATAACTACCTGAAAGGTGTGACCAAGCTGTTC GAACGTATCTACAGC ACGGATCTGGGTCGCATGCTGCTGACTAGCATTGTTCGCGGTATCCCGTTCTGGGGTGGT AGCACGATTGACACC GAACTGAAGGTTATCGACACTAACTGCATTAACGTTATTCAACCGGATGGTAGCTATCGT AGCGAAGAGCTGAAT CTGGTCATCATTGGCCCGAGCGCAGACATTATCCAATTCGAGTGCAAGAGCTTTGGTCAC GAGGTTCTGAATCTG ACCCGCAATGGCTATGGTAGCACCCAGTACATTCGTTTTTCGCCGGATTTTACCTTCGGC TTTGAAGAGAGCCTG GAGGTTGATACCAATCCGTTGCTGGGTGCGGGCAAATTCGCTACCGATCCGGCTGTCACG CTGGCCCATGAACTG ATCCACGCAGGCCACCGCCTGTACGGCATTGCCATCAACCCAAACCGTGTGTTCAAGGTT AATACGAATGCATAC TACGAGATGAGCGGCCTGGAAGTCAGCTTCGAAGAACTGCGCACCTTCGGTGGCCATGAC GCTAAATTCATTGAC AGCTTGCAAGAGAATGAGTTCCGTCTGTACTACTATAACAAATTCAAAGACATTGCAAGC ACGTTGAACAAGGCC AAAAGCATCGTTGGTACTACCGCGTCGTTGCAGTATATGAAGAATGTGTTTAAAGAGAAG TACCTGCTGTCCGAG GATACCTCCGGCAAGTTTAGCGTTGATAAGCTGAAGTTTGACAAACTGTACAAGATGCTG ACCGAGATTTACACC GAGGACAACTTTGTGAAATTCTTCAAAGTGTTGAATCGTAAAACCTATCTGAATTTTGAC AAAGCGGTTTTCAAG ATTAACATCGTGCCGAAGGTGAACTACACCATCTATGACGGTTTTAACCTGCGTAACACC AACCTGGCGGCGAAC TTTAACGGTCAGAATACGGAAATCAACAACATGAATTTCACGAAGTTGAAGAACTTCACG GGTCTGTTCGAGTTC TATAAGCTGCTGTGTCATAAAGCCATTagcggtcgtagcgcaTATAACAAAACCCTGGAT TGCATTAAGGTAAAC AATTGGGATCTGTTCTTTTCGCCATCCGAAGATAATTTTACCAACGACCTGAACAAGGGT GAAGAAATCACCAGC GATACGAATATTGAAGCAGCGGAAGAGAATATCAGCCTGGATCTGATCCAGCAGTACTAT CTGACCTTTAACTTC GACAATGAACCGGAGAACATTAGCATTGAGAATCTGAGCAGCGACATTATCGGTCAGCTG GAACTGATGCCGAAT ATCGAACGTTTCCCGAACGGCAAAAAGTACGAGCTGGACAAGTACACTATGTTCCATTAC CTGCGTGCACAGGAG TTTGAACACGGTAAAAGCCGTATCGCGCTGACCAACAGCGTTAACGAGGCCCTGCTGAAC CCGAGCCGTGTCTAT ACCTTCTTCAGCAGCGACTATGTTAAGAAAGTGAACAAAGCCACTGAGGCCGCGATGTTC CTGGGCTGGGTGGAA CAGCTGGTATATGACTTCACGGACGAGACGAGCGAAGTGAGCACTACCGACAAAATTGCT GATATTACCATCATT ATCCCGTATATTGGTCCGGCACTGAACATTGGCAACATGCTGTACAAAGACGATTTTGTG GGTGCCCTGATCTTC TCCGGTGCCGTGATTCTGCTGGAGTTCATTCCGGAGATTGCGATCCCGGTGTTGGGTACC TTCGCGCTGGTGTCC TACATCGCGAATAAGGTTCTGACGGTTCAGACCATCGATAACGCGCTGTCGAAACGTAAT GAAAAATGGGACGAG GTTTACAAATACATTGTTACGAATTGGCTGGCGAAAGTCAATACCCAGATCGACCTGATC CGTAAGAAAATGAAA GAGGCGCTGGAGAATCAGGCGGAGGCCACCAAAGCAATTATCAACTACCAATACAACCAG TACACGGAAGAAGAG AAGAATAACATTAACTTCAATATCGATGATTTGAGCAGCAAGCTGAATGAATCTATCAAC AAAGCGATGATCAAT ATCAACAAGTTTTTGAATCAGTGTAGCGTTTCGTACCTGATGAATAGCATGATTCCGTAT GGCGTCAAACGTCTG GAGGACTTCGACGCCAGCCTGAAAGATGCGTTGCTGAAATACATTTACGACAATCGTGGT ACGCTGATTGGCCAA GTTGACCGCTTGAAAGACAAAGTTAACAATACCCTGAGCACCGACATCCCATTTCAACTG AGCAAGTATGTTGAT AATCAACGTCTGTTGAGCACTTTCACCGAGTATATCAAAAACATTCTGAACAATATTATC CTGAACCTGCGTTAC AAAGACAACAATCTGATCGATCTGAGCGGCTATGGTGCAAAAGTTGAAGTCTACGACGGT GTCGAACTGAACGAT AAAAACCAGTTCAAACTGACCTCATCGGCTAACTCAAAAATTCGTGTGACGCAGAACCAA AACATCATCTTCAAC TCGGTCTTTCTGGACTTCAGCGTGTCTTTCTGGATTCGCATCCCGAAATATAAAAATGAT GGCATCCAGAACTAC ATCCATAACGAATACACCATCATCAACTGTATGAAAAACAACAGTGGTTGGAAAATTTCC ATCCGTGGCAACCGC ATTATCTGGACCCTGATTGATATCAATGGTAAAACGAAAAGCGTGTTTTTCGAATACAAC ATCCGTGAAGATATC TCTGAATACATCAATCGCTGGTTTTTCGTGACCATTACGAACAATCTGAACAATGCGAAA ATCTATATCAACGGC AAACTGGAAAGTAATACCGACATCAAAGATATTCGTGAAGTTATCGCCAACGGTGAAATC ATCTTCAAACTGGAT GGCGACATCGATCGCACCCAGTTCATTTGGATGAAATACTTCTCCATCTTCAACACGGAA CTGAGTCAGTCCAAT ATCGAAGAACGCTACAAAATCCAATCATACTCGGAATACCTGAAAGATTTCTGGGGTAAC CCGCTGATGTACAAC AAAGAATACTACATGTTCAACGCGGGCAACAAAAACTCATACATCAAACTGAAAAAAGAT TCGCCGGTGGGTGAA ATCCTGACCCGTAGCAAATACAACCAGAACTCTAAATACATCAACTATCGCGATCTGTAC ATTGGCGAAAAATTT ATTATCCGTCGCAAAAGCAACTCTCAGAGTATTAATGATGACATCGTGCGTAAAGAAGAC TACATCTATCTGGAT TTCTTTAATCTGAACCAAGAATGGCGCGTTTATACCTACAAATACTTCAAAAAAGAAGAA ATGAAACTGTTCCTG GCCCCGATTTACGACAGCGATGAATTTTACAACACCATCCAGATCAAAGAATACGATGAA CAGCCGACGTATAGT TGCCAACTGCTGTTCAAAAAAGACGAAGAATCCACCGATGAAATTGGCCTGATTGGTATC CACCGTTTCTATGAA AGCGGTATCGTTTTCGAAGAATACAAAGATTACTTCTGTATCTCTAAATGGTATCTGAAA GAAGTCAAACGCAAA CCGTACAACCTGAAACTGGGCTGCAACTGGCAATTTATCCCGAAAGACGAAGGCTGGACC GAA SEQ ID NO: 157: Exemplary engineered BoNT/A1B1 chimera with modified Cloop/ SGRSA of SEQ ID NO: 65 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKAIS GRSAYNKTLDCIKVN NWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIE NLSSDIIGQLELMPN IERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKK VNKATEAAMFLGWVE QLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFI PEIAIPVLGTFALVS YIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEAT KAIINYQYNQYTEEE KNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDA LLKYIYDNRGTLIGQ VDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNILNNIILNLRYKDNNLIDLSG YGAKVEVYDGVELND KNQFKLTSSANSKIRVTQNQNIIFNSVFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINC MKNNSGWKISIRGNR IIWTLIDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLNNAKIYINGKLESNTDIKD IREVIANGEIIFKLD GDIDRTQFIWMKYFSIFNTELSQSNIEERYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGN KNSYIKLKKDSPVGE ILTRSKYNQNSKYINYRDLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRV YTYKYFKKEEMKLFL APIYDSDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFEEYKD YFCISKWYLKEVKRK PYNLKLGCNWQFIPKDEGWTE LC/A1 is italicised Exogenous activation loop of SEQ ID NO: 65 is bold and underlined H _N B1 is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 158: Nucleic acid encoding exemplary engineered BoNT/A1B1 chimera with modified Cloop/ LTPRGVRL of SEQ ID NO: 57 ATGCCATTCGTCAACAAGCAATTCAACTACAAAGACCCAGTCAACGGCGTCGACATCGCA TACATCAAGATTCCG AACGCCGGTCAAATGCAGCCGGTTAAGGCTTTTAAGATCCACAACAAGATTTGGGTTATC CCGGAGCGTGACACC TTCACGAACCCGGAAGAAGGCGATCTGAACCCGCCACCGGAAGCGAAGCAAGTCCCTGTC AGCTACTACGATTCG ACGTACCTGAGCACGGATAACGAAAAAGATAACTACCTGAAAGGTGTGACCAAGCTGTTC GAACGTATCTACAGC ACGGATCTGGGTCGCATGCTGCTGACTAGCATTGTTCGCGGTATCCCGTTCTGGGGTGGT AGCACGATTGACACC GAACTGAAGGTTATCGACACTAACTGCATTAACGTTATTCAACCGGATGGTAGCTATCGT AGCGAAGAGCTGAAT CTGGTCATCATTGGCCCGAGCGCAGACATTATCCAATTCGAGTGCAAGAGCTTTGGTCAC GAGGTTCTGAATCTG ACCCGCAATGGCTATGGTAGCACCCAGTACATTCGTTTTTCGCCGGATTTTACCTTCGGC TTTGAAGAGAGCCTG GAGGTTGATACCAATCCGTTGCTGGGTGCGGGCAAATTCGCTACCGATCCGGCTGTCACG CTGGCCCATGAACTG ATCCACGCAGGCCACCGCCTGTACGGCATTGCCATCAACCCAAACCGTGTGTTCAAGGTT AATACGAATGCATAC TACGAGATGAGCGGCCTGGAAGTCAGCTTCGAAGAACTGCGCACCTTCGGTGGCCATGAC GCTAAATTCATTGAC AGCTTGCAAGAGAATGAGTTCCGTCTGTACTACTATAACAAATTCAAAGACATTGCAAGC ACGTTGAACAAGGCC AAAAGCATCGTTGGTACTACCGCGTCGTTGCAGTATATGAAGAATGTGTTTAAAGAGAAG TACCTGCTGTCCGAG GATACCTCCGGCAAGTTTAGCGTTGATAAGCTGAAGTTTGACAAACTGTACAAGATGCTG ACCGAGATTTACACC GAGGACAACTTTGTGAAATTCTTCAAAGTGTTGAATCGTAAAACCTATCTGAATTTTGAC AAAGCGGTTTTCAAG ATTAACATCGTGCCGAAGGTGAACTACACCATCTATGACGGTTTTAACCTGCGTAACACC AACCTGGCGGCGAAC TTTAACGGTCAGAATACGGAAATCAACAACATGAATTTCACGAAGTTGAAGAACTTCACG GGTCTGTTCGAGTTC TATAAGCTGCTGtgtcATAAAGCCctgacaccgcgtggtgttcgtctgAAAACCCTGGAT TGCATTAAGGTAAAC AATTGGGATCTGTTCTTTTCGCCATCCGAAGATAATTTTACCAACGACCTGAACAAGGGT GAAGAAATCACCAGC GATACGAATATTGAAGCAGCGGAAGAGAATATCAGCCTGGATCTGATCCAGCAGTACTAT CTGACCTTTAACTTC GACAATGAACCGGAGAACATTAGCATTGAGAATCTGAGCAGCGACATTATCGGTCAGCTG GAACTGATGCCGAAT ATCGAACGTTTCCCGAACGGCAAAAAGTACGAGCTGGACAAGTACACTATGTTCCATTAC CTGCGTGCACAGGAG TTTGAACACGGTAAAAGCCGTATCGCGCTGACCAACAGCGTTAACGAGGCCCTGCTGAAC CCGAGCCGTGTCTAT ACCTTCTTCAGCAGCGACTATGTTAAGAAAGTGAACAAAGCCACTGAGGCCGCGATGTTC CTGGGCTGGGTGGAA CAGCTGGTATATGACTTCACGGACGAGACGAGCGAAGTGAGCACTACCGACAAAATTGCT GATATTACCATCATT ATCCCGTATATTGGTCCGGCACTGAACATTGGCAACATGCTGTACAAAGACGATTTTGTG GGTGCCCTGATCTTC TCCGGTGCCGTGATTCTGCTGGAGTTCATTCCGGAGATTGCGATCCCGGTGTTGGGTACC TTCGCGCTGGTGTCC TACATCGCGAATAAGGTTCTGACGGTTCAGACCATCGATAACGCGCTGTCGAAACGTAAT GAAAAATGGGACGAG GTTTACAAATACATTGTTACGAATTGGCTGGCGAAAGTCAATACCCAGATCGACCTGATC CGTAAGAAAATGAAA GAGGCGCTGGAGAATCAGGCGGAGGCCACCAAAGCAATTATCAACTACCAATACAACCAG TACACGGAAGAAGAG AAGAATAACATTAACTTCAATATCGATGATTTGAGCAGCAAGCTGAATGAATCTATCAAC AAAGCGATGATCAAT ATCAACAAGTTTTTGAATCAGTGTAGCGTTTCGTACCTGATGAATAGCATGATTCCGTAT GGCGTCAAACGTCTG GAGGACTTCGACGCCAGCCTGAAAGATGCGTTGCTGAAATACATTTACGACAATCGTGGT ACGCTGATTGGCCAA GTTGACCGCTTGAAAGACAAAGTTAACAATACCCTGAGCACCGACATCCCATTTCAACTG AGCAAGTATGTTGAT AATCAACGTCTGTTGAGCACTTTCACCGAGTATATCAAAAACATTCTGAACAATATTATC CTGAACCTGCGTTAC AAAGACAACAATCTGATCGATCTGAGCGGCTATGGTGCAAAAGTTGAAGTCTACGACGGT GTCGAACTGAACGAT AAAAACCAGTTCAAACTGACCTCATCGGCTAACTCAAAAATTCGTGTGACGCAGAACCAA AACATCATCTTCAAC TCGGTCTTTCTGGACTTCAGCGTGTCTTTCTGGATTCGCATCCCGAAATATAAAAATGAT GGCATCCAGAACTAC ATCCATAACGAATACACCATCATCAACTGTATGAAAAACAACAGTGGTTGGAAAATTTCC ATCCGTGGCAACCGC ATTATCTGGACCCTGATTGATATCAATGGTAAAACGAAAAGCGTGTTTTTCGAATACAAC ATCCGTGAAGATATC TCTGAATACATCAATCGCTGGTTTTTCGTGACCATTACGAACAATCTGAACAATGCGAAA ATCTATATCAACGGC AAACTGGAAAGTAATACCGACATCAAAGATATTCGTGAAGTTATCGCCAACGGTGAAATC ATCTTCAAACTGGAT GGCGACATCGATCGCACCCAGTTCATTTGGATGAAATACTTCTCCATCTTCAACACGGAA CTGAGTCAGTCCAAT ATCGAAGAACGCTACAAAATCCAATCATACTCGGAATACCTGAAAGATTTCTGGGGTAAC CCGCTGATGTACAAC AAAGAATACTACATGTTCAACGCGGGCAACAAAAACTCATACATCAAACTGAAAAAAGAT TCGCCGGTGGGTGAA ATCCTGACCCGTAGCAAATACAACCAGAACTCTAAATACATCAACTATCGCGATCTGTAC ATTGGCGAAAAATTT ATTATCCGTCGCAAAAGCAACTCTCAGAGTATTAATGATGACATCGTGCGTAAAGAAGAC TACATCTATCTGGAT TTCTTTAATCTGAACCAAGAATGGCGCGTTTATACCTACAAATACTTCAAAAAAGAAGAA ATGAAACTGTTCCTG GCCCCGATTTACGACAGCGATGAATTTTACAACACCATCCAGATCAAAGAATACGATGAA CAGCCGACGTATAGT TGCCAACTGCTGTTCAAAAAAGACGAAGAATCCACCGATGAAATTGGCCTGATTGGTATC CACCGTTTCTATGAA AGCGGTATCGTTTTCGAAGAATACAAAGATTACTTCTGTATCTCTAAATGGTATCTGAAA GAAGTCAAACGCAAA CCGTACAACCTGAAACTGGGCTGCAACTGGCAATTTATCCCGAAAGACGAAGGCTGGACC GAA SEQ ID NO: 159: Exemplary engineered BoNT/A1B1 chimera with modified Cloop/ LTPRGVRL of SEQ ID NO: 57 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKALT PRGVRLKTLDCIKVN NWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIE NLSSDIIGQLELMPN IERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKK VNKATEAAMFLGWVE QLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFI PEIAIPVLGTFALVS YIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEAT KAIINYQYNQYTEEE KNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDA LLKYIYDNRGTLIGQ VDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNILNNIILNLRYKDNNLIDLSG YGAKVEVYDGVELND KNQFKLTSSANSKIRVTQNQNIIFNSVFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINC MKNNSGWKISIRGNR IIWTLIDINGKTKSVFFEYNIREDISEYINRWFFVTITNNLNNAKIYINGKLESNTDIKD IREVIANGEIIFKLD GDIDRTQFIWMKYFSIFNTELSQSNIEERYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGN KNSYIKLKKDSPVGE ILTRSKYNQNSKYINYRDLYIGEKFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRV YTYKYFKKEEMKLFL APIYDSDEFYNTIQIKEYDEQPTYSCQLLFKKDEESTDEIGLIGIHRFYESGIVFEEYKD YFCISKWYLKEVKRK PYNLKLGCNWQFIPKDEGWTE LC/A1 is italicised Exogenous activation loop of SEQ ID NO: 57 is bold and underlined H _N B1 is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 160: Nucleic acid encoding exemplary engineered LC/X- modified Cloop(LTPRGVRL) of SEQ ID NO: 57-H _N /X ATGAAGCTGGAAATCAACAAGTTCAACTATAACGATCCGATCGATGGCATTAACGTTATT ACCATGCGTCCGCCT CGTCATAGCGATAAAATCAATAAAGGTAAAGGTCCGTTCAAAGCCTTTCAGGTGATTAAA AACATTTGGATTGTG CCGGAACGCTACAACTTTACCAATAATACCAACGATCTGAACATTCCGAGCGAACCGATT ATGGAAGCAGATGCC ATTTATAACCCGAACTATCTGAATACCCCGAGCGAAAAAGATGAATTTCTGCAGGGTGTT ATCAAAGTGCTGGAA CGCATTAAAAGCAAACCGGAAGGTGAAAAACTGCTGGAACTGATTAGCAGCAGCATTCCG CTGCCGCTGGTTAGC AATGGTGCACTGACCCTGAGCGATAATGAAACCATTGCATATCAAGAGAACAACAACATT GTGAGCAATCTGCAG GCAAACCTGGTTATTTATGGTCCGGGTCCTGATATTGCAAATAATGCAACCTATGGTCTG TATAGCACCCCGATT AGTAATGGTGAAGGTACACTGAGCGAAGTTAGCTTTAGCCCGTTTTATCTGAAACCGTTT GATGAAAGCTATGGC AATTATCGTAGCCTGGTGAATATCGTGAACAAATTCGTGAAACGTGAATTTGCACCTGAT CCGGCAAGCACCCTG ATGCACCAACTGGTTTATGTTACCCATAATCTGTATGGCATTAGCAACCGCAACTTCTAC TATAACTTTGACACC GGCAAAATTGAAACCAGCCGTCAGCAGAATAGCCTGATTTTTGAAGAACTGCTGACCTTT GGTGGCATTGATAGC AAAGCAATTAGCAGCCTGATCATCAAGAAAATTATCGAAACCGCCAAGAACAACTATACC ACGCTGATTAGCGAA CGCCTGAATACCGTTACCGTTGAAAATGATCTGCTGAAATATATCAAAAACAAAATCCCG GTTCAGGGTCGTCTG GGTAACTTTAAACTGGATACCGCAGAATTCGAGAAAAAGCTGAATACCATTCTGTTTGTG CTGAACGAAAGCAAT CTGGCACAGCGTTTTAGCATTCTGGTTCGTAAACATTACCTGAAAGAACGTCCGATTGAT CCGATTTATGTGAAC ATTCTGGATGACAATAGCTACAGCACCCTGGAAGGTTTTAACATTAGCAGTCAGGGTAGC AATGATTTTCAGGGC CAGCTGCTGGAAAGCAGCTATTTTGAAAAAATTGAATCCAATGCGCTGCGTGCCTTTATC AAAATTtgtcATAAA GCCctgacaccgcgtggtgttcgtctgAAAACCCTGGATTGCATTGAGGTGGAAAACAAA GACCTGTTTCTGATC AGCAATAAAGATAGCCTGAACGATATTAACCTGAGCGAGGAAAAAATCAAACCTGAAACC ACCGTGTTCTTCAAG GATAAACTGCCTCCGCAGGATATTACCCTGTCCAATTATGATTTTACCGAAGCCAATAGC ATCCCGAGCATTAGC CAGCAAAATATTCTGGAACGTAACGAGGAACTGTATGAACCGATTCGTAATAGCCTGTTT GAGATCAAAACCATC TATGTGGACAAACTGACCACCTTTCATTTTCTGGAAGCGCAGAATATTGATGAGAGCATC GATAGCAGCAAAATT CGTGTTGAACTGACCGATAGCGTTGATGAAGCACTGAGCAATCCGAATAAAGTTTATAGC CCGTTCAAGAACATG AGCAACACCATTAATAGCATTGAAACCGGTATTACCAGCACCTACATCTTTTATCAGTGG CTGCGTAGCATCGTG AAAGATTTTAGTGATGAAACGGGCAAAATCGACGTGATTGATAAAAGCAGCGATACCCTG GCAATTGTTCCGTAT ATTGGTCCGCTGCTGAATATTGGTAATGATATTCGTCATGGCGATTTTGTGGGTGCAATT GAACTGGCAGGCATT ACAGCCCTGCTGGAATATGTTCCGGAATTTACCATTCCGATTCTGGTTGGTCTGGAAGTT ATTGGTGGCGAACTG GCACGTGAACAGGTTGAAGCAATTGTTAATAATGCCCTGGATAAACGCGATCAGAAATGG GCAGAAGTTTACAAT ATTACCAAAGCACAGTGGTGGGGCACCATTCATTTACAGATTAATACCCGTCTGGCCCAT ACCTATAAAGCCCTG AGCCGTCAGGCAAATGCCATTAAAATGAATATGGAATTTCAGCTGGCCAACTACAAAGGC AACATTGATGATAAA GCCAAGATCAAAAACGCCATCAGCGAAACCGAAATCCTGCTGAACAAAAGTGTTGAACAG GCCATGAAAAACACC GAGAAGTTTATGATTAAACTGAGCAACAGCTACCTGACCAAAGAAATGATTCCGAAAGTT CAGGACAACCTGAAA AACTTTGATCTGGAAACCAAAAAGACCCTGGACAAGTTCATCAAAGAGAAAGAAGATATT CTGGGCACCAATCTG AGCAGCAGCCTGCGTCGTAAAGTTAGCATTCGTCTGAATAAGAACATTGCCTTCGATATC AACGATATCCCGTTT AGCGAATTCGATGATCTGATCAACCAGTACAAAAATGAA SEQ ID NO: 161: Exemplary engineered LC/X- modified Cloop(LTPRGVRL) of SEQ ID NO: 57-H _N /X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHQLVYVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICHKALTPRGVRLK TLDCIEVENKDLFLI SNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSISQQNILERNEE LYEPIRNSLFEIKTI YVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKNMSNTINSIETG ITSTYIFYQWLRSIV KDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAGITALLEYVPEF TIPILVGLEVIGGEL AREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKALSRQANAIKMN MEFQLANYKGNIDDK AKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETKKTL DKFIKEKEDILGTNL SSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNE LC/X is italicised Exogenous activation loop of SEQ ID NO: 57 is bold and underlined H _N X is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 162: Nucleic acid encoding exemplary engineered LC/X- modified Cloop(SGRSA) of SEQ ID NO: 65-HN/X ATGAAGCTGGAAATCAACAAGTTCAACTATAACGATCCGATCGATGGCATTAACGTTATT ACCATGCGTCCGCCT CGTCATAGCGATAAAATCAATAAAGGTAAAGGTCCGTTCAAAGCCTTTCAGGTGATTAAA AACATTTGGATTGTG CCGGAACGCTACAACTTTACCAATAATACCAACGATCTGAACATTCCGAGCGAACCGATT ATGGAAGCAGATGCC ATTTATAACCCGAACTATCTGAATACCCCGAGCGAAAAAGATGAATTTCTGCAGGGTGTT ATCAAAGTGCTGGAA CGCATTAAAAGCAAACCGGAAGGTGAAAAACTGCTGGAACTGATTAGCAGCAGCATTCCG CTGCCGCTGGTTAGC AATGGTGCACTGACCCTGAGCGATAATGAAACCATTGCATATCAAGAGAACAACAACATT GTGAGCAATCTGCAG GCAAACCTGGTTATTTATGGTCCGGGTCCTGATATTGCAAATAATGCAACCTATGGTCTG TATAGCACCCCGATT AGTAATGGTGAAGGTACACTGAGCGAAGTTAGCTTTAGCCCGTTTTATCTGAAACCGTTT GATGAAAGCTATGGC AATTATCGTAGCCTGGTGAATATCGTGAACAAATTCGTGAAACGTGAATTTGCACCTGAT CCGGCAAGCACCCTG ATGCACCAACTGGTTTATGTTACCCATAATCTGTATGGCATTAGCAACCGCAACTTCTAC TATAACTTTGACACC GGCAAAATTGAAACCAGCCGTCAGCAGAATAGCCTGATTTTTGAAGAACTGCTGACCTTT GGTGGCATTGATAGC AAAGCAATTAGCAGCCTGATCATCAAGAAAATTATCGAAACCGCCAAGAACAACTATACC ACGCTGATTAGCGAA CGCCTGAATACCGTTACCGTTGAAAATGATCTGCTGAAATATATCAAAAACAAAATCCCG GTTCAGGGTCGTCTG GGTAACTTTAAACTGGATACCGCAGAATTCGAGAAAAAGCTGAATACCATTCTGTTTGTG CTGAACGAAAGCAAT CTGGCACAGCGTTTTAGCATTCTGGTTCGTAAACATTACCTGAAAGAACGTCCGATTGAT CCGATTTATGTGAAC ATTCTGGATGACAATAGCTACAGCACCCTGGAAGGTTTTAACATTAGCAGTCAGGGTAGC AATGATTTTCAGGGC CAGCTGCTGGAAAGCAGCTATTTTGAAAAAATTGAATCCAATGCGCTGCGTGCCTTTATC AAAATTTGTCATAAA GCCATTagcggtcgtagcgcaTATAACAAAACCCTGGATTGCATTGAGGTGGAAAACAAA GACCTGTTTCTGATC AGCAATAAAGATAGCCTGAACGATATTAACCTGAGCGAGGAAAAAATCAAACCTGAAACC ACCGTGTTCTTCAAG GATAAACTGCCTCCGCAGGATATTACCCTGTCCAATTATGATTTTACCGAAGCCAATAGC ATCCCGAGCATTAGC CAGCAAAATATTCTGGAACGTAACGAGGAACTGTATGAACCGATTCGTAATAGCCTGTTT GAGATCAAAACCATC TATGTGGACAAACTGACCACCTTTCATTTTCTGGAAGCGCAGAATATTGATGAGAGCATC GATAGCAGCAAAATT CGTGTTGAACTGACCGATAGCGTTGATGAAGCACTGAGCAATCCGAATAAAGTTTATAGC CCGTTCAAGAACATG AGCAACACCATTAATAGCATTGAAACCGGTATTACCAGCACCTACATCTTTTATCAGTGG CTGCGTAGCATCGTG AAAGATTTTAGTGATGAAACGGGCAAAATCGACGTGATTGATAAAAGCAGCGATACCCTG GCAATTGTTCCGTAT ATTGGTCCGCTGCTGAATATTGGTAATGATATTCGTCATGGCGATTTTGTGGGTGCAATT GAACTGGCAGGCATT ACAGCCCTGCTGGAATATGTTCCGGAATTTACCATTCCGATTCTGGTTGGTCTGGAAGTT ATTGGTGGCGAACTG GCACGTGAACAGGTTGAAGCAATTGTTAATAATGCCCTGGATAAACGCGATCAGAAATGG GCAGAAGTTTACAAT ATTACCAAAGCACAGTGGTGGGGCACCATTCATTTACAGATTAATACCCGTCTGGCCCAT ACCTATAAAGCCCTG AGCCGTCAGGCAAATGCCATTAAAATGAATATGGAATTTCAGCTGGCCAACTACAAAGGC AACATTGATGATAAA GCCAAGATCAAAAACGCCATCAGCGAAACCGAAATCCTGCTGAACAAAAGTGTTGAACAG GCCATGAAAAACACC GAGAAGTTTATGATTAAACTGAGCAACAGCTACCTGACCAAAGAAATGATTCCGAAAGTT CAGGACAACCTGAAA AACTTTGATCTGGAAACCAAAAAGACCCTGGACAAGTTCATCAAAGAGAAAGAAGATATT CTGGGCACCAATCTG AGCAGCAGCCTGCGTCGTAAAGTTAGCATTCGTCTGAATAAGAACATTGCCTTCGATATC AACGATATCCCGTTT AGCGAATTCGATGATCTGATCAACCAGTACAAAAATGAA SEQ ID NO: 163: Exemplary engineered LC/X- modified Cloop(SGRSA) of SEQ ID NO: 65-HN/X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHQLVYVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICHKAISGRSAYNK TLDCIEVENKDLFLI SNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSISQQNILERNEE LYEPIRNSLFEIKTI YVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKNMSNTINSIETG ITSTYIFYQWLRSIV KDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAGITALLEYVPEF TIPILVGLEVIGGEL AREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKALSRQANAIKMN MEFQLANYKGNIDDK AKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETKKTL DKFIKEKEDILGTNL SSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNE LC/X is italicised Exogenous activation loop of SEQ ID NO: 65 is bold and underlined HNX is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 164: Nucleic acid encoding exemplary engineered LC/X- modified Cloop(PPFGRSAG) of SEQ ID NO: 63-H _N /X ATGAAGCTGGAAATCAACAAGTTCAACTATAACGATCCGATCGATGGCATTAACGTTATT ACCATGCGTCCGCCT CGTCATAGCGATAAAATCAATAAAGGTAAAGGTCCGTTCAAAGCCTTTCAGGTGATTAAA AACATTTGGATTGTG CCGGAACGCTACAACTTTACCAATAATACCAACGATCTGAACATTCCGAGCGAACCGATT ATGGAAGCAGATGCC ATTTATAACCCGAACTATCTGAATACCCCGAGCGAAAAAGATGAATTTCTGCAGGGTGTT ATCAAAGTGCTGGAA CGCATTAAAAGCAAACCGGAAGGTGAAAAACTGCTGGAACTGATTAGCAGCAGCATTCCG CTGCCGCTGGTTAGC AATGGTGCACTGACCCTGAGCGATAATGAAACCATTGCATATCAAGAGAACAACAACATT GTGAGCAATCTGCAG GCAAACCTGGTTATTTATGGTCCGGGTCCTGATATTGCAAATAATGCAACCTATGGTCTG TATAGCACCCCGATT AGTAATGGTGAAGGTACACTGAGCGAAGTTAGCTTTAGCCCGTTTTATCTGAAACCGTTT GATGAAAGCTATGGC AATTATCGTAGCCTGGTGAATATCGTGAACAAATTCGTGAAACGTGAATTTGCACCTGAT CCGGCAAGCACCCTG ATGCACCAACTGGTTTATGTTACCCATAATCTGTATGGCATTAGCAACCGCAACTTCTAC TATAACTTTGACACC GGCAAAATTGAAACCAGCCGTCAGCAGAATAGCCTGATTTTTGAAGAACTGCTGACCTTT GGTGGCATTGATAGC AAAGCAATTAGCAGCCTGATCATCAAGAAAATTATCGAAACCGCCAAGAACAACTATACC ACGCTGATTAGCGAA CGCCTGAATACCGTTACCGTTGAAAATGATCTGCTGAAATATATCAAAAACAAAATCCCG GTTCAGGGTCGTCTG GGTAACTTTAAACTGGATACCGCAGAATTCGAGAAAAAGCTGAATACCATTCTGTTTGTG CTGAACGAAAGCAAT CTGGCACAGCGTTTTAGCATTCTGGTTCGTAAACATTACCTGAAAGAACGTCCGATTGAT CCGATTTATGTGAAC ATTCTGGATGACAATAGCTACAGCACCCTGGAAGGTTTTAACATTAGCAGTCAGGGTAGC AATGATTTTCAGGGC CAGCTGCTGGAAAGCAGCTATTTTGAAAAAATTGAATCCAATGCGCTGCGTGCCTTTATC AAAATTTGTCATAAA GCCATTCCGCCGTTTGGTCGTAGCGCAGGTTATAACAAAACCCTGGATTGTATTGAGGTG GAAAACAAAGACCTG TTTCTGATCAGCAATAAAGATAGCCTGAACGATATTAACCTGAGCGAGGAAAAAATCAAA CCTGAAACCACCGTG TTCTTCAAGGATAAACTGCCTCCGCAGGATATTACCCTGTCCAATTATGATTTTACCGAA GCCAATAGCATCCCG AGCATTAGCCAGCAAAATATTCTGGAACGTAACGAGGAACTGTATGAACCGATTCGTAAT AGCCTGTTTGAGATC AAAACCATCTATGTGGACAAACTGACCACCTTTCATTTTCTGGAAGCGCAGAATATTGAT GAGAGCATCGATAGC AGCAAAATTCGTGTTGAACTGACCGATAGCGTTGATGAAGCACTGAGCAATCCGAATAAA GTTTATAGCCCGTTC AAGAACATGAGCAACACCATTAATAGCATTGAAACCGGTATTACCAGCACCTACATCTTT TATCAGTGGCTGCGT AGCATCGTGAAAGATTTTAGTGATGAAACGGGCAAAATCGACGTGATTGATAAAAGCAGC GATACCCTGGCAATT GTTCCGTATATTGGTCCGCTGCTGAATATTGGTAATGATATTCGTCATGGCGATTTTGTG GGTGCAATTGAACTG GCAGGCATTACAGCCCTGCTGGAATATGTTCCGGAATTTACCATTCCGATTCTGGTTGGT CTGGAAGTTATTGGT GGCGAACTGGCACGTGAACAGGTTGAAGCAATTGTTAATAATGCCCTGGATAAACGCGAT CAGAAATGGGCAGAA GTTTACAATATTACCAAAGCACAGTGGTGGGGCACCATTCATTTACAGATTAATACCCGT CTGGCCCATACCTAT AAAGCCCTGAGCCGTCAGGCAAATGCCATTAAAATGAATATGGAATTTCAGCTGGCCAAC TACAAAGGCAACATT GATGATAAAGCCAAGATCAAAAACGCCATCAGCGAAACCGAAATCCTGCTGAACAAAAGT GTTGAACAGGCCATG AAAAACACCGAGAAGTTTATGATTAAACTGAGCAACAGCTACCTGACCAAAGAAATGATT CCGAAAGTTCAGGAC AACCTGAAAAACTTTGATCTGGAAACCAAAAAGACCCTGGACAAGTTCATCAAAGAGAAA GAAGATATTCTGGGC ACCAATCTGAGCAGCAGCCTGCGTCGTAAAGTTAGCATTCGTCTGAATAAGAACATTGCC TTCGATATCAACGAT ATCCCGTTTAGCGAATTCGATGATCTGATCAACCAGTACAAAAATGAA SEQ ID NO: 165: Exemplary engineered LC/X- modified Cloop(PPFGRSAG) of SEQ ID NO: 63-HN/X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHQLVYVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICHKAIPPFGRSAG YNKTLDCIEVENKDL FLISNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSISQQNILER NEELYEPIRNSLFEI KTIYVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKNMSNTINSI ETGITSTYIFYQWLR SIVKDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAGITALLEYV PEFTIPILVGLEVIG GELAREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKALSRQANAI KMNMEFQLANYKGNI DDKAKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETK KTLDKFIKEKEDILG TNLSSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNE LC/X is italicised Exogenous activation loop of SEQ ID NO: 63 is bold and underlined H _N X is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 166: Exemplary engineered LC/A1- modified Cloop(LTPRGVRL) of SEQ ID NO: 57-HN/A1 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKALT PRGVRLKTLDCIKVN NWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIE NLSSDIIGQLELMPN IERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKK VNKATEAAMFLGWVE QLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFI PEIAIPVLGTFALVS YIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEAT KAIINYQYNQYTEEE KNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDA LLKYIYDNRGTLIGQ VDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKN LC/A1 is italicised Exogenous activation loop of SEQ ID NO: 57 is bold and underlined HNA1 is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 167: Exemplary engineered LC/A1- modified Cloop(PPFGRSAG) of SEQ ID NO: 63-HN/A1 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKAIP PFGRSAGYNKTLDCI KVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENI SIENLSSDIIGQLEL MPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDY VKKVNKATEAAMFLG WVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILL EFIPEIAIPVLGTFA LVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQA EATKAIINYQYNQYT EEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASL KDALLKYIYDNRGTL IGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKN LC/A1 is italicised Exogenous activation loop of SEQ ID NO: 63 is bold and underlined H _NA1 is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 168: Exemplary engineered LC/A1- modified Cloop(SGRSA) of SEQ ID NO: 65-HN/A1 MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCHKAIS GRSAYNKTLDCIKVN NWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIE NLSSDIIGQLELMPN IERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKK VNKATEAAMFLGWVE QLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFI PEIAIPVLGTFALVS YIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEAT KAIINYQYNQYTEEE KNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDA LLKYIYDNRGTLIGQ VDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKN LC/A1 is italicised Exogenous activation loop of SEQ ID NO: 65 is bold and underlined H _NA1 is C-terminal to the activation loop and is neither underlined nor italicised SEQ ID NO: 169: Preferred thrombin consensus sequence (AL)X(PLAG)(RK)|(SAG)(AVL)(GL)X wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). SEQ ID NO: 170: Preferred thrombin consensus sequence (AL)XPR|G(AVL)(GL)X wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). SEQ ID NO: 171: Preferred motif within a thrombin cleavage site PRG SEQ ID NO: 172: Preferred uPA and/or t-PA consensus sequence P(GPAL)(SGF)(GS)(RK)|(SGV)(AVLR) wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). SEQ ID NO: 173: Preferred uPA and/or t-PA consensus sequence P(GPAL)(SGF)GR|SA wherein each X may be independently selected from any amino acid, the amino acid residues shown in parentheses are alternative possible amino acid residues at each position, wherein the bold and underlined residues are preferred. The “|” shows the site of cleavage (i.e. the peptide bond that is hydrolysed). SEQ ID NO: 174: Preferred motif within a uPA and/or t-PA cleavage site GRSA SEQ ID NO: 175 Exemplary nucleic acid encoding LC/X-Cloop-HN/X atgaagctggaaatcaacaagttcaactataacgatccgatcgatggcattaacgttatt accatgcgtccgcct cgtcatagcgataaaatcaataaaggtaaaggtccgttcaaagcctttcaggtgattaaa aacatttggattgtg ccggaacgctacaactttaccaataataccaacgatctgaacattccgagcgaaccgatt atggaagcagatgcc atttataacccgaactatctgaataccccgagcgaaaaagatgaatttctgcagggtgtt atcaaagtgctggaa cgcattaaaagcaaaccggaaggtgaaaaactgctggaactgattagcagcagcattccg ctgccgctggttagc aatggtgcactgaccctgagcgataatgaaaccattgcatatcaagagaacaacaacatt gtgagcaatctgcag gcaaacctggttatttatggtccgggtcctgatattgcaaataatgcaacctatggtctg tatagcaccccgatt agtaatggtgaaggtacactgagcgaagttagctttagcccgttttatctgaaaccgttt gatgaaagctatggc aattatcgtagcctggtgaatatcgtgaacaaattcgtgaaacgtgaatttgcacctgat ccggcaagcaccctg atgcacgagctggttcatgttacccataatctgtatggcattagcaaccgcaacttctac tataactttgacacc ggcaaaattgaaaccagccgtcagcagaatagcctgatttttgaagaactgctgaccttt ggtggcattgatagc aaagcaattagcagcctgatcatcaagaaaattatcgaaaccgccaagaacaactatacc acgctgattagcgaa cgcctgaataccgttaccgttgaaaatgatctgctgaaatatatcaaaaacaaaatcccg gttcagggtcgtctg ggtaactttaaactggataccgcagaattcgagaaaaagctgaataccattctgtttgtg ctgaacgaaagcaat ctggcacagcgttttagcattctggttcgtaaacattacctgaaagaacgtccgattgat ccgatttatgtgaac attctggatgacaatagctacagcaccctggaaggttttaacattagcagtcagggtagc aatgattttcagggc cagctgctggaaagcagctattttgaaaaaattgaatccaatgcgctgcgtgcctttatc aaaatttgtcataaa gccattgatggtcgcagcctgtataacaaaaccctggattgtattgaggtggaaaacaaa gacctgtttctgatc agcaataaagatagcctgaacgatattaacctgagcgaggaaaaaatcaaacctgaaacc accgtgttcttcaag gataaactgcctccgcaggatattaccctgtccaattatgattttaccgaagccaatagc atcccgagcattagc cagcaaaatattctggaacgtaacgaggaactgtatgaaccgattcgtaatagcctgttt gagatcaaaaccatc tatgtggacaaactgaccacctttcattttctggaagcgcagaatattgatgagagcatc gatagcagcaaaatt cgtgttgaactgaccgatagcgttgatgaagcactgagcaatccgaataaagtttatagc ccgttcaagaacatg agcaacaccattaatagcattgaaaccggtattaccagcacctacatcttttatcagtgg ctgcgtagcatcgtg aaagattttagtgatgaaacgggcaaaatcgacgtgattgataaaagcagcgataccctg gcaattgttccgtat attggtccgctgctgaatattggtaatgatattcgtcatggcgattttgtgggtgcaatt gaactggcaggcatt acagccctgctggaatatgttccggaatttaccattccgattctggttggtctggaagtt attggtggcgaactg gcacgtgaacaggttgaagcaattgttaataatgccctggataaacgcgatcagaaatgg gcagaagtttacaat attaccaaagcacagtggtggggcaccattcatttacagattaatacccgtctggcccat acctataaagccctg agccgtcaggcaaatgccattaaaatgaatatggaatttcagctggccaactacaaaggc aacattgatgataaa gccaagatcaaaaacgccatcagcgaaaccgaaatcctgctgaacaaaagtgttgaacag gccatgaaaaacacc gagaagtttatgattaaactgagcaacagctacctgaccaaagaaatgattccgaaagtt caggacaacctgaaa aactttgatctggaaaccaaaaagaccctggacaagttcatcaaagagaaagaagatatt ctgggcaccaatctg agcagcagcctgcgtcgtaaagttagcattcgtctgaataagaacattgccttcgatatc aacgatatcccgttt agcgaattcgatgatctgatcaaccagtacaaaaatgaa nucleic acid encoding the Cloop is bold and underlined nucleic acid encoding 2xAP linker is dash underlined SEQ ID NO: 176: Exemplary nucleic acid Cloop tgtcataaagccattgatggtcgcagcctgtataacaaaaccctggat EXAMPLES The invention will be further illustrated by the following examples, which are intended to be purely exemplary of the invention and are in no way limiting. In addition to the data presented below, the contents of PCT/GB2022/050756, and in particular the examples section, is incorporated herein by reference. Although that case concerns engineered clostridial neurotoxins comprising furin cleavage sites, rather than exogenous protease cleavage sites, it nevertheless contains data obtained from engineered clostridial neurotoxins with features in common with those of the present invention, as well as relevant synthetic methods. Example 1 – design and production of engineered BoNT comprising exogenous protease cleavage sites Engineered BoNT were produced by determining the desired amino acid sequence, back-translating this to the corresponding nucleic acid sequence followed by codon optimisation for recombinant expression in bacteria. The resulting gene sequences were checked to ensure no commonly-used restriction sites (NdeI, XhoI, BamHI, HindIII, NcoI, and EcoRI) were present within the sequence. A start codon was added at the 5’ end, a stop codon at the 3’ end, and appropriate terminal restriction sites (e.g. an NdeI restriction site to the 5’ end and BamHI restriction site at the 3’ end) to enable subcloning into expression vectors. The gene sequences for the engineered BoNT were then subcloned into a pK8 vector (which comprises a kanamycin resistance gene, a T7 promoter, a T7 terminator, a pBR322 origin of replication, and a multiple cloning site). The plasmid for each engineered BoNT was then amplified in E. coli strain DH5α with kanamycin selection, and extracted by miniprep using standard molecular biology techniques. E. coli expression strain BL21 with λDE3 was then transformed with the plasmid DNA, spread onto agar supplemented with kanamycin, and incubated overnight at 37 °C. Colonies were then harvested and used to prepare a glycerol stock. A stab was then used to inoculate 100 mL of modified TB media supplemented kanamycin, followed by incubation at 37 °C overnight with shaking at 225 RPM to provide aeration.10 mL of this starter culture was used to inoculate several baffled conical flasks, each containing up to 1 L of the same nutrient media and antibiotic. The cultures were grown under the same conditions for a few hours to an optical density (A600) of ≥0.6 and then set the incubator temperature to 16 °C. The cultures were then induced to express the engineered BoNTs by addition of IPTG an hour later. After 20 hours, the cells were harvested by centrifugation and stored at -80 °C before use. The cells were thawed in 0.25 M NaCl in 50 mM Tris pH 7.4 (5 mL/g cells) and lysed at 4 °C by either two passes through a cell homogenisor at 20k PSI or by ultrasonication (10x 30 s on/off). Cell debris was removed by centrifugation and the clarified supernatant loaded onto a nickel affinity column pre-equilibrated with 0.5 M NaCl in 50 mM Tris pH 7.4 (“Buffer NA”) using an FPLC system (GE). The column was washed with Buffer NA until a steady baseline at A280 was achieved. The wash and elute proteins were collected off the column with a linear gradient of 0-0.5 M imidazole in Buffer NA in over 25 column volumes (CV) while collecting 3 mL fractions. All collected material was stored at 4 °C while analysing samples by SDS PAGE with staining (Invitrogen). Fractions showing a protein strong band at the calculated MW of the target molecule based on the protein marker were pooled, and the total protein concentration measured using a Nanodrop (Thermo Fisher). The pooled fractions were desalted into 50 mM Tris pH 8 (“Buffer QA”) for further purification by anionic exchange chromatography (e.g., Q HP). After washing the column with Buffer QA to a steady baseline, proteins were eluted with a linear gradient of 0-0.5 M NaCl in Buffer QA over 25 CV. Samples were analysed by SDS-PAGE and fractions containing pure target desalted into 150 mM NaCl in 50 mM HEPES pH 7.2 before dividing into aliquots for storage at -80 °C. Analysis of a sample of the final product in the presence and absence of DTT by SDS PAGE showed a single band The above method was used to produce X engineered BoNT with the structure LC/A1- ExoLoop-H _N /A1-TM: When ExoLoop = modified C loop comprising a KRV cleavage site (A4952), modified C loop comprising a GRI cleavage site (A49523) and modified C loop comprising a PRG cleavage site (A4954). All three of these engineered BoNT comprise the same targeting moiety (TM), BoNT/A1 light chain (LC/A1), and BoNT/A1 translocation domain (H _N /A1), but with different modified C loops comprising different exogenous protease cleavage sites. The pre-engineering LC/A1-Cloop-H _N /A1 sequence for each of these engineered BoNT is SEQ ID NO: 150, in which the Cloop (SEQ ID NO: 2) has been replaced by a modified C loop. In particular, A4952 comprises the modified C loop of SEQ ID NO: 53, which itself comprises a cleavage site KRV which is specific for u-PA and t-PA. A49523 comprises the modified C loop of SEQ ID NO: 55, which itself comprises a cleavage site GRI which is specific for. FIX and FVII. A49524 comprises the modified C loop of SEQ ID NO: 54, which itself comprises a cleavage site PRG which is specific for thrombin. Example 2 – BoNT engineered to comprise an KRV modified C-loop are effectively cleaved by u-PA A4952 from Example 1 was incubated with incubated with increasing concentrations of urokinase ((i) 1µl, giving a final u-PA concentration of 0.85µg/mL; (ii) 5µl, giving a final u- PA concentration of 4.22µg/mL; and (iii) 10µl, giving a final u-PA concentration of 8.41µg/mL). Samples taken at time 3hrs, 4hrs, 5hrs and 19hrs after the reaction start time were analysed by SDS PAGE under reducing and non-reducing conditions. As can be seen in Figure 1A, at the higher concentrations of uPA (4.22µg/mL; and 8.41µg/mL), some cleavage of A4952 was observed as early 3hrs. By 19hrs, cleavage was observed at all concentrations of u-PA tested. The table below sets out the lanes of the gels in Figure 1A: Example 3 – BoNT engineered to comprise a GRI modified C-loop were not effectively cleaved by FIX A4953 from Example 1 was incubated with incubated with increasing concentrations of FIX ((i) 1µl, giving a final FIX concentration of 1µg/mL; (ii) 5µl, giving a final FIX concentration of 5µg/mL; and (iii) 10µl, giving a final FIX concentration of 10µg/mL). Samples taken at time 1hr, 2hrs, 3hrs and 19hrs after the reaction start time were analysed by SDS PAGE under reducing and non-reducing conditions. As can be seen in Figure 2, no cleavage of A4953 was observed, even at the higher concentrations of FIX and a reaction time of 19hrs. The table below sets out the lanes of the gels in Figure 2: Example 4 – BoNT engineered to comprise an PRG modified C-loop are effectively cleaved by thrombin A4954 from Example 1 was incubated with incubated with increasing concentrations of thrombin ((i) 1µl, giving a final thrombin concentration of 0.46µg/mL; (ii) 5µl, giving a final thrombin concentration of 2.3µg/mL; and (iii) 10µl, giving a final thrombin concentration of 4.6g/mL). Samples taken at time 1hr, 2hrs, 3hrs, 4hrs and 19hrs after the reaction start time were analysed by SDS PAGE under reducing and non-reducing conditions. As can be seen in Figure 3A, cleavage was observed after 1hr even at the lowest concentration of thrombin (0.46µg/mL), and by 19hrs complete cleavage of A4954 was observed for the higher thrombin concentrations (2.3µg/mL and 4.6g/mL). The table below sets out the lanes of the gels in Figure 3A: The resulting cleaved A4954 products were analysed by mass spectrometry. Samples were desalted using thermo ZEBA 0.5m 7K MWCO spin columns. Columns were prepared by 3 X washes with 300µl 100mM tris prior to thawing of samples. After desalting protein concentration was measured on nanodrop and the concentration was corrected to a concentration of 0.1 AU and 1 µl DTT was added per 99 µl of sample and was incubated for 30 minutes at 37°C. Samples were then analysed by LC/MS. The HPLC column used was a BioResolve, RP mAb Polyphenyl 450Å 2.7µm 2.1X150 mm, S/N 01153907216925. One microlitre of sample was injected. Samples were analysed using the method SXNA004472 Bioresolve sensitivity 6 mins segmented gradient as described in NBK88-86. As shown in Figure 3B, a single cleavage site was identified within the activation loop, at residue R437. In addition, no off-site cleavage of A4954 by thrombin was observed. Further, the same modified C loop comprising a PRG cleavage site as present in A4954 was used to replace the BoNT/A activation loop in a further three retargeted BoNTs, each with the LC/A1-ExoLoop-H _N /A1-TM architecture, but with different targeting moieties (A00005361, A00005362 and A00005363). As shown in Figure 3C, in each case thrombin was able to cleave the PGR cleavage site within the modified C loop, with no truncation products being visible. The table below sets out the lanes of the gels in Figure 3C: Example 5 – Design of additional exogenous activation loops and modified BoNT/C1 activation loops The methodology of Example 1 was used to generate engineered BoNTs with the same LC/A1-ExoLoop-HN/A1-TM architecture as Example 1, but with exogenous activation loops and modified BoNT/C1 activation loops as shown in the table below. ▼= cleavage site Example 6 – BoNTs engineered to comprise an ENKSLVPRGS modified C-loop or an SGRSA modified C-loop are effectively cleaved by thrombin and urokinase respectively 200 µg of engineered BoNT with an ENKSLVPRGS modified C-loop was treated with increasing amounts of (i) thrombin (0.39µg, 1.95µg and 3.90µg) at 20°C and samples taken at 2, 4 and 20 hours post-activation. 200 µg of engineered BoNT with an SGRSA modified C-loop was treated with increasing amounts of (i) urokinase; (ii) a functional t-PA fragment (t-PAfrag); or (iii) full-length t-PA (t-PAfl) at increasing concentrations (0.39µg, 1.95µg and 3.90µg) at 20°C and samples taken at 2, 4 and 20 hours post-activation. As shown in Figure 4A, at 2 hours, cleavage of the engineered BoNT with an ENKSLVPRGS modified C-loop with thrombin was nearly complete, even at the lowest concentration of thrombin tested. The heavy and light chains are visible (black arrows) on the non-reducing gel. Cleavage of the engineered BoNT with an SGRSA modified C-loop had begun at 2 hours with urokinase at 0.39µg, with trace amounts of a possible truncation product (dotted arrow). However, there was no observable cleavage of the engineered BoNT with an SGRSA modified C-loop with either t-PA. The table below sets out the lanes of the gels in Figure 4A: Cleavage progressed over the time course, and by 4 hours thrombin cleavage of the engineered BoNT with an ENKSLVPRGS modified C-loop was nearly complete at all concentrations of thrombin tested (not shown). Cleavage of the engineered BoNT with an SGRSA modified C-loop was almost complete with urokinase at 0.39µg, with trace amounts of a possible truncation product (not shown). By 20 hours, cleavage of the engineered BoNT with an ENKSLVPRGS modified C- loop with thrombin nearly complete at all concentrations of thrombin tested. Cleavage of the engineered BoNT with an SGRSA modified C-loop was almost complete with urokinase at 0.39µg. However, there was only trace cleavage of the engineered BoNT with an SGRSA modified C-loop with either t-PA. The results of cleaving the engineered BoNT with an SGRSA modified C-loop with urokinase were compared with the urokinase cleavage of A4952 from Example 2. Compared with the KVR cleavage site, inclusion of a SGRSA cleavage site in a modified C-loop resulted in improved cleavage and specificity, and less off target activity. Thus, these results suggest that an SGRSA modified C-loop may be advantageous when engineering BoNTs for urokinase activation, compared with a KVR modified C-loop. The results of cleaving the engineered BoNT with an ENKSLVPRGS modified C-loop with thrombin were compared with the thrombin cleavage of A4954 from Example 4. Compared with the PRG cleavage site, inclusion of a ENKSLVPRGS cleavage site in a modified C-loop increased the rate of cleavage, with no observable off target activity. Thus, these results suggest that an ENKSLVPRGS modified C-loop may be advantageous when engineering BoNTs for thrombin activation, compared with a PRG modified C-loop. Furthermore, even 72hrs after thrombin activation (at 20°C, pH7.2, 150mM NaCl), there was no observable truncation of the engineered BoNT with an ENKSLVPRGS modified C-loop, even when the concentration of thrombin was increased 10-fold (19.5µg) (data not shown). This suggests that the ENKSLVPRGS modified C-loop would advantageously facilitate engineered BoNT stability, e.g. during manufacturing delays. The resulting products from cleaving the engineered BoNT with an SGRSA modified C-loop (A5045) were analysed by mass spectrometry. Samples were desalted using thermo ZEBA 0.5m 7K MWCO spin columns. Columns were prepared by 3 X washes with 300µl 100mM tris prior to thawing of samples. After desalting protein concentration was measured on nanodrop and the concentration was corrected to a concentration of 0.1 AU and 1 µl DTT was added per 99 µl of sample and was incubated for 30 minutes at 37°C. Samples were then analysed by LC/MS. The HPLC column used was a BioResolve, RP mAb Polyphenyl 450Å 2.7µm 2.1X150 mm, S/N 01153907216925. One microlitre of sample was injected. Samples were analysed using the method SXNA004472 Bioresolve sensitivity 6 mins segmented gradient as described in NBK88-86. As shown in Figure 4B, a single cleavage site was identified within the activation loop, at residue R437. Two off-site cleavages of A5045 were observed, at residues F167 and K683, both of which are potentially amenable to removal by genetic engineering. Example 7 – Design of further exogenous activation loops and modified BoNT/C1 activation loops Based on the experimental results observed in Example 6, the methodology of Example 1 was used to generate further engineered BoNTs with the same LC/A1-ExoLoop- HN/A1-TM architecture as Example 1, but with further exogenous protease cleavage sites as shown in the table below introduced into a C-loop. ▼= cleavage site Example 8 – BoNTs engineered to comprise an LTPRGVRL modified C-loop, a PGSGRSAG modified C-loop or a PPFGRSAG modified C-loop are effectively cleaved by thrombin, urokinase and/or t-PA respectively 200 µg of engineered BoNT with an LTPRGVRL modified C-loop was treated with increasing amounts of (i) thrombin (0.39µg, 1.95µg and 3.90µg) at 20°C and pH7.2 and samples taken at 2, 4 and 20 hours post-activation. 200 µg of engineered BoNT with an PGSGRSAG modified C-loop or an extended PGSGRSAG modified C-loop (comprising PGSGRSASGTTGTG) was treated with increasing amounts of (i) urokinase; (ii) a functional fragment of t-PA (t-PAfrag); or (iii) full-length t-PA (t- PAfl) at increasing concentrations (0.39µg, 1.95µg and 3.90µg) at 20°C and pH7.2 and samples taken at 2, 4 and 20 hours post-activation. 200 µg of engineered BoNT with an PPFGRSAG modified C-loop was treated with increasing amounts of (i) urokinase; (ii) t-PAfrag; or (iii) t-PAfl at increasing concentrations (0.39µg, 1.95µg and 3.90µg) at 20°Cand pH7.2 and samples taken at 2, 4 and 20 hours post- activation. As shown in Figure 5A, at 2 hours, cleavage of the engineered BoNT with an LTPRGVRL modified C-loop with thrombin was nearly complete, even at the lowest concentration of thrombin tested. Cleavage was essentially complete by 4 hours (data not shown). By 20 hours some truncation was observed, following extended incubation after activation had been completed. The table below sets out the lanes of the gels in Figure 5A: As shown in Figure 5B, at 2 hours, cleavage of the engineered BoNT with a PGSGRSAG modified C-loop with urokinase was underway, even at the lowest concentration of urokinase tested, with significant activation already achieved when 1.95µg or 3.90µg urokinase was used. Compared with the engineered BoNT with a SGRSA modified C-loop, the rate of activation by urokinase of the PGSGRSAG modified C-loop engineered BoNT was increased. Cleavage of the PGSGRSAG modified C-loop engineered BoNTs was essentially complete by 4 hours when 1.95µg or 3.90µg urokinase was used. Trace amounts of a possible urokinase-produced truncation product (black arrow) were observed at all time points. However, there was no observable cleavage of the engineered BoNT with a PGSGRSAG modified C-loop with t-PA _frag or t-PA _fl . The table below sets out the lanes of the gels in Figure 5B: As shown in Figure 5C, at 2 hours, cleavage of the engineered BoNT with a PGSGRSASGTTGTG modified C-loop with urokinase was underway, even at the lowest concentration of urokinase tested, with significant activation already achieved when 1.95µg or 3.90µg urokinase was used. Cleavage of the PGSGRSASGTTGTG modified C-loop engineered BoNTs was essentially complete by 4 hours when 3.90µg urokinase was used. Trace amounts of a possible urokinase-produced truncation product (black arrow) were observed at all time points. However, there was no observable cleavage of the engineered BoNT with a PGSGRSASGTTGTG modified C-loop with t-PA _frag or t-PA _fl . The table below sets out the lanes of the gels in Figure 5C: As shown in Figure 5D, at 2 hours, cleavage of the engineered BoNT with a PPFGRSAG modified C-loop with was underway with each of urokinase, t-PAfrag and t-PAfl. With urokinase, some activation was observed even at the lowest concentration of urokinase tested. For with t-PA _frag and t-PA _fl some activation was achieved when 1.95µg or 3.90µg t- PA _frag or t-PA _fl was used. Cleavage of the PPFGRSAG modified C-loop engineered BoNTs progressed over time, such that by 20 hours significant cleavage was observed for all of urokinase, t-PA _frag and t-PA _fl at each concentration tested. No truncation products produced using t-PA _frag or t-PA _fl were observed at any time points. The table below sets out the lanes of the gels in Figure 5D: The cleavage experiment was repeats with engineered BoNT with an PPFGRSAG modified C-loop and increasing concentrations of t-PA _frag and t-PA _fl . 200 µg of engineered BoNT with an PPFGRSAG modified C-loop was treated with t-PAfrag or t-PAfl at increasing concentrations (3.9µg, 7.8µg, 15.6µg and 31.2µg) at 20°Cand pH7.2 and samples taken at 2, 4 and 20 hours post-activation. As shown in Figure 5E, increasing concentrations t-PAfrag and t-PAfl increased cleavage of the engineered BoNT with a PPFGRSAG modified C-loop at each time point, with almost complete activation being observed with higher concentrations. Even with these increased concentrations of t-PA _frag and t-PA _fl , no truncation products produced using t-PAfrag and t-PAfl were observed at any time points. The table below sets out the lanes of the gels in Figure 5E: Discussion The ENKSLVPRGS and LTPRGVRL modified C-loops were highly effective, indicating that they have potential to be used to increase activation and/or reduce the amount of protease required for activation. Further, minimal truncation was observed in the range of engineered BoNTs tested, with trace truncation being observed only at 20 hours, when activation was complete by 4 hours. Furthermore, thrombin appears to be compatible with BoNT/X based engineered molecules (data not shown) Therefore, use of thrombin, particularly with ENKSLVPRGS and LTPRGVRL modified C-loops, and most preferably a LTPRGVRL modified C-loop is a commercially preferred option. For activation with urokinase, the SGRSA and PGSGRSAG modified C-loops show improved cleavage with urokinase. The PGSGRSASGTTGTG modified C-loop also shows improvement over the KRV modified C-loop for urokinase. Whilst some truncation products were observed, they could potentially be managed during the production and purification process, and/or the susceptible sites within BoNT backbones could potentially be removed by further engineering. For activation with t-PA, the VVPRVELVA modified C-loop shows no evidence of cleavage by any of the proteases tested. The SGRSA modified C-loop and extended PGSGRSASGTTGTG modified C-loop show some cleavage with t-PA variants (t-PAfrag & t- PAfl), and the PPFGRSAG modified C-loop shows reasonable activation at higher concentrations with the t-PA variants. Significantly, no truncation of the SGRSA modified C- loop, extended PGSGRSASGTTGTG modified C-loop or PPFGRSAG modified C-loop was observed, even at high concentrations of the t-PA variants. All publications mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and system of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in biochemistry and biotechnology or related fields are intended to be within the scope of the following claims.