CLOSTRIDIAL NEUROTOXINS COMPRISING AN ACTIVATING ENDOSOMAL PROTEASE CLEAVAGE SITE FIELD OF THE INVENTION The present invention relates to clostridial neurotoxins engineered to comprise an endosomal protease cleavage site within the 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 Endosomes are small membrane-bound vesicles inside eukaryotic cells, endosomes are involved in transporting material that has been internalised from outside a cell. Some endosomes maintain an acidic pH, which can dissociate proteins from receptors. Once separated, these different components can be trafficked. Some molecules are targeted for recycling back to the cell surface, while others fuse with lysosomes, where contents are degraded by hydrolase enzymes. Endosomes also traffic material to and from the Golgi, or between apical and basal compartments in polarized cells. Endosomes contain numerous proteases, which degrade internalised proteins. 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). This represented a paradigm shift in terms of clostridial neurotoxin production, processing and activation, and indeed therapeutic use. In particular, to the extent that attempts have previously been made in the art to introduce exogenous cleavage sites into clostridial neurotoxins, the goal had always been to facilitate in vitro production and processing of clostridial neurotoxins which are then administered in di- chain form. The present inventors have now demonstrated that this potential for in vivo activation of clostridial neurotoxins is not limited to the use of furin, but rather that other endogenous proteases, particularly endosomal proteases such as Cathepsin L and asparaginyl endopeptidase (AEP) are also capable of cleaving appropriate cleavage sites that have been exogenously introduced to clostridial neurotoxins. In addition, the endosomal protease-activated engineered clostridial neurotoxins of the invention offer several potential benefits compared with conventionally activated clostridial neurotoxins, such as improving the safety of operators (e.g. clinicians or others handling the endosomal protease-activated engineered neurotoxins of the invention in order to administer to patients, and workers involved in the production of the endosomal protease-activated engineered neurotoxins), and/or reducing manufacturing burden/costs. The endosomal protease-activated engineered neurotoxins of the invention also have potentially increased safety profiles for patients. Thus, the inventors provide for the first time that single-chain clostridial neurotoxins, such as engineered BoNT/A1 with a endosomal protease cleavage site with therapeutic potential, without requiring activation to di-chain form prior to administration. Accordingly, the invention provides an engineered clostridial neurotoxin, comprising an endosomal protease cleavage site, wherein cleavage at said cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. The endosomal protease cleavage site may be a cleavage site specific for: (a) asparagine endopeptidase (AEP); or (b) a cathepsin, optionally cathepsin L1, B, D, K or S. The endosomal protease cleavage site may comprise or consist of: (a) an APE core motif selected from SEQ ID NO: 208-214; (b) a cathepsin L core motif selected from SEQ ID NOs: 138 and/or 188-197; (c) a cathepsin B core motif selected from SEQ ID NOs: 20, 181, 198 and/or 199; and/or (d) a cathepsin D core motif selected from SEQ ID NOs: 200-207. The endosomal protease cleavage site may comprise or consist of one or more of: SEQ ID NOs: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186 and/or 187. The engineered clostridial neurotoxin may comprise an exogenous activation loop which comprises or consists of any one of SEQ ID NOs: 35, 36, 37, 38, 127, 128 and/or 129. An endogenous activation loop of a clostridial neurotoxin, or part thereof, may be replaced by one or more endosomal protease cleavage site according to the invention. Said endogenous neurotoxin activation loop may be one or more selected from SEQ ID NO: 89 to 112. 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. Preferably the clostridial neurotoxin is BoNT/X, BoNT/A (e.g. BoNT/A1) or BoNT/B. In particularly preferred embodiments the clostridial neurotoxin is BoNT/X. The engineered clostridial neurotoxin may be a single-chain clostridial neurotoxin: (a) encoded by a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 163, wherein SEQ ID NO: 164 within SEQ ID NO: 163 is replaced by a nucleotide sequence encoding at least one endosomal protease cleavage site, which is optionally selected from SEQ ID NOs: 165, 166 and 167; and/or (b) comprising a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. 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). Preferably, the engineered clostridial neurotoxin may be a re-targeted BoNT/X or BoNT/A. The invention also provides an engineered retargeted BoNT/X comprising an endosomal protease cleavage site, which comprises a polypeptide sequence having at least 70% sequence identity, preferably at least 80%, more preferably at least 90%, even more preferably at least 95% sequence identity to SEQ ID NO: 160-162. The invention further provides a method for proteolytically processing an engineered clostridial neurotoxin according to the invention into a corresponding di-chain clostridial neurotoxin, the method comprising contacting the engineered clostridial neurotoxin with an endosomal protease specific for the endosomal protease cleavage site, thereby producing a di-chain clostridial neurotoxin. The invention also provides a di-chain clostridial neurotoxin obtainable by said method. The invention further provides a polynucleotide encoding an engineered clostridial neurotoxin according to the invention. The invention also provides an expression vector comprising a polynucleotide as defined in claim 15, which is operably linked to a promoter. Said polynucleotide or expression vector may: comprise or consist of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 163, wherein SEQ ID NO: 164 within SEQ ID NO: 163 is replaced by a nucleotide sequence encoding at least one endosomal protease cleavage site, which is optionally selected from SEQ ID NOs: 165, 166 and 167; and/or (b) encode a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. The invention also provides a method of producing an engineered clostridial neurotoxin of the invention, comprising the step of expressing a polynucleotide 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 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 or expression vector of the invention. The invention further 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 also provides an engineered clostridial neurotoxin, a di-chain clostridial neurotoxin, 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, a di-chain clostridial neurotoxin, 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. Said engineered clostridial neurotoxin (e.g. within a pharmaceutical composition) 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. The invention also provides a cosmetic composition comprising an engineered clostridial neurotoxin, 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. Said 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 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. 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 endosomal protease; wherein the single-chain clostridial neurotoxin has an activation loop comprising or consisting of a polypeptide sequence as defined herein; and wherein the endosomal protease hydrolyses a peptide bond of the activation loop thereby producing a di-chain clostridial neurotoxin. The single-chain clostridial neurotoxin may be: (a) an engineered clostridial neurotoxin of the invention; (b) encoded by a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 163, wherein SEQ ID NO: 164 within SEQ ID NO: 163 is replaced by a nucleotide sequence encoding at least one endosomal protease cleavage site, which is optionally selected from SEQ ID NOs: 165, 166 and 167; and/or (c) comprise a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: (A) Coomassie staining of purified unprocessed CatDReo (BIO4934), Ebo (BIO4935), CatBL (BIO4945) and AEP (BIO4938) at pH 5 and 7.2. (B) Western blot analysis with αLC/A antibody of purified unprocessed CatDReo (BIO4934), Ebo (BIO4935), CatBL (BIO4945) and AEP (BIO4938) at pH 5 and 7.2. Figure 2: (A) Coomassie staining (left panel), Western blot analysis with αLC/A antibody (middle panel) and Western blot analysis with αHis antibody (right panel) of CatDReo (BIO4934), incubated with a serial dilution of Cathepsin L1 reduced with DTT and resolved by SDS PAGE. (B) Coomassie staining (left panel), Western blot analysis with αLC/A antibody (middle panel) and Western blot analysis with αHis antibody (right panel) of Ebo (BIO4935), incubated with a serial dilution of Cathepsin L1 reduced with DTT and resolved by SDS PAGE. Figure 3: (A) Coomassie staining, (B) Western blot analysis with αLC/A antibody and Western blot analysis with αHis antibody (C) of CatBL (BIO4945), incubated with a serial dilution of Cathepsin B reduced with DTT and resolved by SDS PAGE. Figure 4: (A) Coomassie staining, (B) Western blot analysis with αLC/A antibody and Western blot analysis with αHis antibody (C) of AEP (BIO4938), incubated with a serial dilution of AEP reduced with DTT and resolved by SDS PAGE. 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 defined herein, the term “endosome” refers to a membrane-delineated intracellular organelle. Endosomes are typically part of the endocytic membrane transport pathway originating from the trans Golgi network. The term “endosome” encompasses early endosomes, late endosomes and recycling endosomes unless expressly stated to the contrary. The term “endosome” may also encompass lysosomes and/or other intracellular vesicles. Each of these “early”, “late”, “recycling” and “lysosomal” compartments is characterised by a distinct protein–lipid composition, morphology, and intraluminal pH, Early endosomes are typically up to 1 µm (e.g.100 – 500 nm) in diameter, and may be connected by tubules of about 50 nm in diameter. Markers for early endosomes may include RAB5A and RAB4, RAB11, transferrin and early endosome antigen 1 (EEA1). Late endosomes are typically spherical and not connected by tubules. Late endosomes may comprise multiple close-packed intraluminal vesicles. Markers for late endosomes may include RAB7, RAB9, and mannose 6-phosphate receptors. The late endosomal membrane (and lysosomes) may contain named lysobisphosphatidic acid (LBPA). As acidificiation occurs as endosomes mature, typically late endosomes have lower pH (pH approx 5.0) than early endosomes (pH approx 6.5). Recycling endosomes are concentrated at the microtubule organizing centre and consist of a mainly tubular network. Markers for recycling endosomes include RAB11 and RAB4. Lysosomes are small vesicles derived from the Golgi apparatus which contain up to 50 different degradative enzymes. Lysosomes typically have the lowest pH out of any intracellular vesicular compartment (pH approx 4.5-5.0), which acidic pH is required for the enzymes therein to function. Lysosomal markers include highly glycosylated, lysosome- associated membrane proteins (LAMPs), for example, LAMP-1 and LAMP-2, and RAB9. 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 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: 153). Non-limiting examples of GS linkers include GS5 or (GGGGS)1 (SEQ ID NO: 154); GS10 or (GGGGS)2 (SEQ ID NO: 155); GS15 or (GGGGS)3 (SEQ ID NO: 156); GS20 or (GGGGS)4 (SEQ ID NO: 157); and GS25 or(GGGGS)5 (SEQ ID NO: 158). As used herein, the term “core motif” refers to a minimal amino acid sequence which can be cleaved by a given endosomal protease. By way of non-limiting example, a core motif for Cathepsin L defines a minimum amino acid sequence which can be cleaved by Cathepsin L. There may exist more than one core motif for any given endosomal protease. 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. 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 endosomal protease cleavage site. Typically cleavage at said endosomal protease cleavage site results in the production of a di-chain form of the engineered clostridial neurotoxin. In other words, cleavage at the endosomal protease cleavage site results in activation of an engineered clostridial neurotoxin. The endogenous (native) activation loop of a clostridial neurotoxin may be replaced (or partially replaced) by an endosomal protease cleavage site. As such the term “endosomal protease cleavage site” may be used interchangeably with the terms “endosomal protease activation site”, and an exogenous activation loop as defined herein will typically comprise or consist of one or more endosomal protease cleavage site, as described herein. The engineered clostridial neurotoxins of the invention 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 clostridial neurotoxin (pre-engineering) is typically characterised in that the endogenous activation loop is inefficiently proteolytically processed by one or more endosomal 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 endosomal 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 endosomal protease. Thus, the clostridial neurotoxin (pre- engineering) is typically resistant to proteolytic processing by one or more endosomal protease. The terms “inefficiently proteolytically processed by one or more endosomal protease”, “resistant to proteolytic processing by one or more endosomal protease”, “not substantially hydrolysed by one or more endosomal protease” “inefficiently activated by one or more endosomal protease”, “resistant to activation by one or more endosomal protease” and “not substantially activated by one or more endosomal protease” are used interchangeably herein. Typically, the clostridial neurotoxin (pre-engineering) is typically resistant to proteolytic processing by the one or more endosomal 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 endosomal 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 endosomal 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 endosomal protease in a method of the invention. Accordingly, a clostridial neurotoxin (pre-engineering) may not contain one or more endosomal protease cleavage site (e.g. as defined herein, such as any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187) within its endogenous activation loop. A clostridial neurotoxin (pre-engineering) may not contain one or more endosomal protease core motif (e.g. as defined herein, such as any one of SEQ ID NOs: 20, 138, 181 and/or 188-214). A clostridial neurotoxin (pre-engineering) may not contain one or more endosomal protease cleavage site (e.g. as defined herein, such as any one of SEQ ID NOs: 1 to 38, 130- 152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130- 152 or 171-187) and/or one or more endosomal protease core motif (e.g. as defined herein, such as any one of SEQ ID NOs: 20, 138, 181 and/or 188-214) for an endosomal 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 Cathepsin L cleavage site, then the corresponding pre-engineering clostridial neurotoxin may not comprise a Cathepsin L cleavage site and/or core motif within its endogenous activation loop. In some embodiments wherein the one or more endosomal protease cleavage site comprises an AEP cleavage site, the (pre-engineering) clostridial neurotoxin may be a BoNT/B, BoNT/C or BoNT/F, particularly a BoNT/B or BoNT/C. In particularly preferred embodiments the clostridial neurotoxin is BoNT/X or a chimera or hybrid of BoNT/X with another clostridial neurotoxin. The invention may comprise replacing an endogenous activation loop (or part thereof) of any clostridial neurotoxin with one or more endosomal protease (exogenous) cleavage site or an exogenous activation loop comprising one or more endosomal 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/C ₁ , BoNT/D, BoNT/E, BoNT/F, BoNT/G or BoNT/X, or a chimeric or hybrid thereof.. In 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 does not comprise or consist of one or more endosomal protease cleavage sites as described herein (e.g. SEQ ID NOs: 1 to 38; SEQ ID NOs: 12 to 38; SEQ ID NOs: 1 to 34; or SEQ ID NOs: 12 to 34). An “endogenous activation loop” is any activation loop that is does not comprise or consist of one or more endosomal protease cleavage sites selected from (i) SEQ ID NOs: 1-10, 12-21 or 27- 38; (ii) SEQ ID NOs: 12-21 or 27-38; (iii) SEQ ID NOs: 1-10, 12-21 or 17-34; or (iv) SEQ ID NOs: 12-21 or 27-34). 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 endosomal protease cleavage site. For 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. 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 H _N domain are derived. For example, where the L-chain is a BoNT/B L-chain and the H _N 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 endosomal 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 endosomal protease cleavage site, or by an exogenous activation loop which comprises one or more endosomal protease cleavage site. Typically according to the invention one or more endosomal protease cleavage site is 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 endosomal 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. The entire endogenous activation loop may be replaced by one or more endosomal protease cleavage site or an exogenous activation loop comprising one or more endosomal 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. In some 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 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 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 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 of an endogenous activation loop 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 endosomal protease cleavage site or an exogenous activation loop comprising one or more endosomal 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 endosomal protease cleavage site or the exogenous activation loop comprising the one or more endosomal 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 endosomal 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 endosomal 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 endosomal protease cleavage site, and as such may be activated either by the native activating protease (or equivalents used in recombinant BoNT production, e.g., trypsin or Lys- C), or by one or more endosomal protease. 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: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111 or SEQ ID NO: 112. 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: 112. In particular, an endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111 or SEQ ID NO: 112. In particular, an endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 112. Preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111 or SEQ ID NO: 112. Preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 112. 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: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95 or SEQ ID NO: 96. An endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95 or SEQ ID NO: 96. Preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95 or SEQ ID NO: 96. 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: 94. An endogenous activation loop may comprise or consist of a polypeptide sequence having at least 95% sequence identity to SEQ ID NO: 94. More preferably, an endogenous activation loop comprises or consists of a polypeptide sequence shown as SEQ ID NO: 94. The present invention encompasses methods and clostridial neurotoxins in which an endogenous activation loop has been replaced by an exogenous cleavage site, which is one or more endosomal protease cleavage site, or an exogenous activation loop which comprises one or more endosomal 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 endosomal 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 endosomal 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 endosomal protease cleavage site or exogenous activation loop comprising said one or more endosomal protease cleavage site has five amino acids. If ten amino acids are replaced in an endogenous activation loop, the replacement one or more endosomal protease cleavage site or exogenous activation loop comprising said one or more endosomal protease cleavage site has ten amino acids. Non-limiting examples of such exogenous activation loops include CQEAANERQQAKKDFFSSHPLREPVNATEDPDLKNVKSGLTNIKTELVTPARDLFGFVGL F RGHHPDC (SEQ ID NO: 127), CQLGKNEEGLFGFVGLFRGHHPDELVTPARDFGHFGLSGLTNIKTEC (SEQ ID NO: 128) and/or CPGGGNKKIELVTPARDLFGFVGLFRGHHPDLKNVKSKC (SEQ ID NO: 129), or corresponding sequences lacking the N- and/or C-terminal cysteine residues, as the remaining sequences may be inserted within the endogenous cysteine residues of the pre- engineering clostridial neurotoxin. all of which are derived from the BoNT/A1 activation loop. 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, thereby providing an engineered clostridial neurotoxin, wherein the exogenous cleavage site is one or more endosomal protease cleavage site as described herein, or the exogenous activation loop comprises said one or more endosomal protease cleavage site. Typically said one or more endosomal protease cleavage site is selected from a sequence which comprises or consists of the amino acid sequence of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187, or the exogenous activation loop comprises said one or more endosomal 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 or an exogenous cleavage site, thereby providing an engineered clostridial neurotoxin, wherein the exogenous cleavage site is one or more endosomal protease cleavage site as described herein, or the exogenous activation loop comprises said one or more endosomal protease cleavage site. Typically said one or more endosomal protease cleavage site is selected from a sequence which comprises or consists of the amino acid sequence of SEQ ID NO: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187, or the exogenous activation loop comprises said one or more endosomal protease cleavage site, such as any one of SEQ ID NOs: 127-129. A clostridial neurotoxin of the present invention (e.g., engineered clostridial neurotoxin) may be encoded by a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 163, and wherein the nucleotide sequence encoding the BoNT/C activation loop (SEQ ID NO: 164) is replaced by a nucleic acid encoding the one or more endosomal protease site or the exogenous activation loop comprising said one or more endosomal cleavage sites. A clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) may be encoded by a nucleotide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 163, wherein the nucleotide sequence encoding the BoNT/C activation loop (SEQ ID NO: 164) is replaced by a nucleic acid encoding the one or more endosomal protease site or the exogenous activation loop comprising said one or more endosomal cleavage sites. Preferably a clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) is encoded by a nucleotide sequence of SEQ ID NO: 163, wherein the nucleic acid encoding the BoNT/C activation loop (SEQ ID NO: 164) is replaced by a nucleotide sequence encoding the one or more endosomal protease site or the exogenous activation loop comprising said one or more endosomal cleavage sites. Non-limiting examples of nucleotide sequences encoding exogenous activation loops which may replace SEQ ID NO: 164 within SEQ ID NO: 163 include SEQ ID NOs: 165, 166 and 167. Thus, by way of non-limiting example, a clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) may be encoded by a nucleotide sequence of SEQ ID NOs: 168, 169 and 170. A clostridial neurotoxin of the present invention (e.g., engineered clostridial neurotoxin) may comprise a polypeptide sequence having at least 70% sequence identity to one or more of SEQ ID NOs: 121 or 159- 162. A clostridial neurotoxin of the present invention may comprise a polypeptide sequence having at least 80% or 90% sequence identity to one or more of SEQ ID NOs: 121 or 159- 162. Preferably, a clostridial neurotoxin of the present invention may comprise (more preferably consist of) a polypeptide sequence shown as any one of SEQ ID NOs: 121 or 159- 162 The clostridial neurotoxin of the present invention (e.g. engineered clostridial neurotoxin) is preferably a retargeted BoNT/X, wherein the clostridial neurotoxin is encoded by a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 163, wherein SEQ ID NO: 164 within SEQ ID NO: 163 is replaced by a nucleotide sequence encoding at least one endosomal protease cleavage site, which is optionally selected from SEQ ID NOs: 165, 166 and 167. The clostridial neurotoxin may be encoded by a nucleotide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 163, wherein SEQ ID NO: 164 within SEQ ID NO: 163 is replaced by a nucleotide sequence encoding at least one endosomal protease cleavage site, which is optionally selected from SEQ ID NOs: 165, 166 and 167. Preferably the clostridial neurotoxin is encoded by a nucleotide sequence comprising (or consisting of) SEQ ID NO: 163, wherein SEQ ID NO: 164 within SEQ ID NO: 163 is replaced by a nucleotide sequence encoding at least one endosomal protease cleavage site, which is optionally selected from SEQ ID NOs: 165, 166 and 167. The clostridial neurotoxin of the present invention is preferably a re-targeted BoNT/X, wherein the clostridial neurotoxin comprises a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. The clostridial neurotoxin may comprise a polypeptide sequence having at least 80% sequence identity to SEQ ID NO: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. The clostridial neurotoxin may comprise a polypeptide sequence having at least 90% sequence identity to SEQ ID NO: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. Preferably the clostridial neurotoxin comprises (or consists of) a polypeptide sequence shown as SEQ ID NO: 120, wherein SEQ ID NO: 91 within SEQ ID NO: 120 is replaced by at least one endosomal protease cleavage site or exogenous activation loop, which is optionally selected from SEQ ID NOs: 127-129. 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. Endosomal Proteases and Endosomal Protease Cleavage Sites Endosomes and lysosomes can comprise multiple different proteases, herein referred to as “endosomal proteases” (also referred to interchangeably as endolysosymal proteases). In other words, the term “endosomal protease” as used herein refers to proteases which may be contained in endosome, lysosomes or both. These endosomal proteases have a variety of different functions, and are typically involved in the degradation of proteins and peptides taken up by endosomes from outside the cell. These enzymes are readily available commercially. Non-limiting examples of endosomal proteases according to the invention include cathepsin and asparagine endopeptidase (AEP, also referred to as asparaginyl endopeptidase or legumain). The term “Cathepsin” describes a family of endosomal proteases, including cathepsin A, cathepsin B, cathepsin C, cathepsin D, cathepsin E, cathepsin F, cathepsin G, cathepsin H, cathepsin K, cathepsin L, cathepsin O, cathepsin S, cathepsin V, cathepsin W and cathepsin Z. Preferably the invention relates to cathepsin L (e.g., L1), B, D, K or S, and/or AEP. In other words, engineered clostridial neurotoxins of the invention typically comprises at least one cleavage site for one or more of cathepsin L (e.g., L1), B, D, K or S, and/or AEP. Cathepsin L1 is a thiol protease with similar specificity to papain, cleaving in a range of consensus sequences, including Xaa1-Xaa2-Leu/Val/Phe/Ile-Xaa3 // Xaa4-Xaa5-Xaa6-Xaa7, where Xaa1-7 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “cathepsin L1” encompasses cathepsin L1 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 Xaa1-Xaa2-Leu/Val/Phe/Ile-Xaa3 // Xaa4-Xaa5-Xaa6-Xaa7. A suitable cathepsin L1 is human cathepsin L1, which has UniProt Accession No. P07711 (version 2 of the sequence, deposited 01 October 1989, accessed 30 July 2022), herein SEQ ID NO: 39. 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 1-113. Human cathepsin L1 is commercially available from Merck (#SRP6416). Cathepsin B is a thiol protease with similar specificity to papain, cleaving in a range of consensus sequences, including (i) cleaving after the second arginine residue in the consensus Arg-Arg-Xaa, where X is any amino acid and/or (ii) Xaa ₁ -Xaa ₂ -Xaa ₃ -Gly // Xaa ₄ - Xaa ₅ -Gly-Xaa ₆ , 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 “cathepsin B” encompasses cathepsin B 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-Arg-Xaa or Xaa ₁ -Xaa ₂ -Xaa ₃ -Gly // Xaa ₄ - Xaa ₅ -Gly-Xaa ₆ . A suitable cathepsin B is human cathepsin B, which has UniProt Accession No. P07858 (version 3 of the sequence, deposited 21 June 2005, accessed 30 July 2022), herein SEQ ID NO: 40. 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 1-79. Human cathepsin B is commercially available from Merck (#SRP0289). Cathepsin D is a thiol protease with similar specificity to pepsin A, cleaving in a range of consensus sequences, including Xaa ₁ -Xaa ₂ -Xaa ₃ -Leu/Phe // Xaa ₄ -Xaa ₅ -Xaa ₆ -Xaa ₇ , where Xaa _1-7 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “cathepsin D” encompasses cathepsin D 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 Xaa1-Xaa2-Xaa3-Leu/Phe // Xaa4-Xaa5-Xaa6-Xaa7. A suitable cathepsin D is human cathepsin D, which has UniProt Accession No. P07339 (version 1 of the sequence, deposited 01 April 1988, accessed 30 July 2022), herein SEQ ID NO: 41. 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 1-64. Human cathepsin D is commercially available from Merck (#SRP6415). Cathepsin K is a thiol protease with broad proteolytic activity. The primary determinant of specificity is P2 in the standard nomenclature (P4-P3-P2-P1 // P1’-P2’-P3’-P4’), which may preferably be Leu, Met or Phe, and not Arg. Cathepsin K cleaves in a range of consensus sequences, including Xaa1-Xaa2-Leu/Ile/Val/Pro-Xaa3 // Xaa4-Xaa5-Xaa6-Xaa7, where Xaa1-7 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “cathepsin K” encompasses cathepsin K 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 Xaa1-Xaa2-Leu/Ile/Val/Pro-Xaa3 // Xaa4-Xaa5-Xaa6-Xaa7. A suitable cathepsin K is human cathepsin K, which has UniProt Accession No. P43235 (version 1 of the sequence, deposited 01 November 1995, accessed 30 July 2022), herein SEQ ID NO: 42. 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 1-114. Human cathepsin K is commercially available from Merck (#SRP6561). Cathepsin S is a thiol protease with broad proteolytic activity. Cathepsin S cleaves in a range of consensus sequences, including Xaa ₁ -Xaa ₂ -Leu/Val-Xaa ₃ // Xaa ₄ -Xaa ₅ -Xaa ₆ -Xaa ₇ , where Xaa _1-7 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “cathepsin S” encompasses cathepsin S 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 -Leu/Val-Xaa ₃ // Xaa ₄ -Xaa ₅ -Xaa ₆ -Xaa ₇ . A suitable cathepsin S is human cathepsin S, which has UniProt Accession No. P25774 (version 3 of the sequence, deposited 21 February 2006, accessed 30 July 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 1-114. Human cathepsin S is commercially available from Merck (# SRP6297). AEP has strict specificity for hydrolysis of asparaginyl and aspartyl bonds. Thus, AEP cleaves in a range of consensus sequences comprising such a bond (Asn/Asp // Xaa, where Xaa may be any amino acid) which in the standard nomenclature may be represented as Xaa1-Xaa2-Xaa3-Asn/Asp // Xaa4-Xaa5-Xaa6-Xaa7, where Xaa1-7 may each be independently selected from any amino acid, and wherein “//” indicates the position of the hydrolysed peptide bond. The term “AEP” encompasses AEP described herein, as well as any protease having structural and/or functional similarity (preferably structural and functional similarity) that is capable of hydrolysing asparaginyl and/or aspartyl bonds. A suitable AEP is human AEP, which has UniProt Accession No. Q99538 (version 1 of the sequence, deposited 01 May 1997, accessed 30 July 2022), herein SEQ ID NO: 44. Human AEP is commercially available from Jena Bioscience (# PR-967S or # PR-967L). Other exemplary cathepsins include cathepsin A (e.g. UniProt Accession No. P10619, version 2 of the sequence, deposited 16 April 2002, accessed 30 July 2022), cathepsin C (e.g. UniProt Accession No. P53634, version 2 of the sequence, deposited 11 January 2011, accessed 30 July 2022), cathepsin E (e.g. UniProt Accession No. P14091, version 3 of the sequence, deposited 28 March 2018, accessed 30 July 2022), cathepsin F (e.g. UniProt Accession No. Q9UBX1, version 1 of the sequence, deposited 01 May 2000, accessed 30 July 2022), cathepsin G (e.g. UniProt Accession No. P08311, version 2 of the sequence, deposited 01 January 1990, accessed 30 July 2022), cathepsin H (e.g. UniProt Accession No. P09668, version 4 of the sequence, deposited 09 February 2010, accessed 30 July 2022), cathepsin O (e.g. UniProt Accession No. P43234, version 1 of the sequence, deposited 01 November 1995, accessed 30 July 2022), cathepsin V (e.g. UniProt Accession No. O60911, version 2 of the sequence, deposited 01 December 2000, accessed 30 July 2022), cathepsin W (e.g. UniProt Accession No. P56202, version 2 of the sequence, deposited 22 September 2009, accessed 30 July 2022) and cathepsin Z (e.g. UniProt Accession No. Q9UBR2, version 1 of the sequence, deposited 01 May 2000, accessed 30 July 2022). 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 endosomal protease to activate an engineered clostridial neurotoxin of the invention under standard/desired conditions. In the context of the invention the term “cathepsin L (e.g., L1)” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 39, or the mature form thereof. Thus, “cathepsin L (e.g., L1)” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 39, or the mature form thereof. Preferably a cathepsin L (e.g., L1) comprises (more preferably consists of) SEQ ID NO: 39, or the mature form thereof. In the context of the invention the term “cathepsin B” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 40, or the mature form thereof. Thus, “cathepsin B” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 40, or the mature form thereof. Preferably a cathepsin B comprises (more preferably consists of) SEQ ID NO: 40, or the mature form thereof. In the context of the invention the term “cathepsin D” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 41, or the mature form thereof. Thus, “cathepsin D” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 41, or the mature form thereof. Preferably a cathepsin D comprises (more preferably consists of) SEQ ID NO: 41, or the mature form thereof. In the context of the invention the term “cathepsin K” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 42, or the mature form thereof. Thus, “cathepsin K” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 42, or the mature form thereof. Preferably a cathepsin K comprises (more preferably consists of) SEQ ID NO: 42, or the mature form thereof. In the context of the invention the term “cathepsin S” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 43, or the mature form thereof. Thus, “cathepsin S” 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 cathepsin S comprises (more preferably consists of) SEQ ID NO: 43, or the mature form thereof. In the context of the invention the term “AEP” encompasses a polypeptide sequence having at least 70% sequence identity to SEQ ID NO: 44. Thus, “AEP” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to SEQ ID NO: 44. Preferably an AEP comprises (more preferably consists of) SEQ ID NO: 44. In the context of the invention the term “cathepsin A” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P10619 as described herein, or the mature form thereof. Thus, “cathepsin A” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P10619 as described herein, or the mature form thereof. Preferably a cathepsin A comprises (more preferably consists of) UniProt Accession No. P10619 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin C” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P53634 as described herein, or the mature form thereof. Thus, “cathepsin C” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P53634 as described herein, or the mature form thereof. Preferably a cathepsin C comprises (more preferably consists of) UniProt Accession No. P53634 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin E” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P14091 as described herein, or the mature form thereof. Thus, “cathepsin E” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P14091 as described herein, or the mature form thereof. Preferably a cathepsin E comprises (more preferably consists of) UniProt Accession No. P14091 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin F” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. Q9UBX1 as described herein, or the mature form thereof. Thus, “cathepsin F” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. Q9UBX1 as described herein, or the mature form thereof. Preferably a cathepsin F comprises (more preferably consists of) UniProt Accession No. Q9UBX1 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin G” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P08311 as described herein, or the mature form thereof. Thus, “cathepsin G” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P08311 as described herein, or the mature form thereof. Preferably a cathepsin G comprises (more preferably consists of) UniProt Accession No. P08311 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin H” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P09668 as described herein, or the mature form thereof. Thus, “cathepsin H” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P09668 as described herein, or the mature form thereof. Preferably a cathepsin H comprises (more preferably consists of) UniProt Accession No. P09668 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin O” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P43234 as described herein, or the mature form thereof. Thus, “cathepsin O” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P43234 as described herein, or the mature form thereof. Preferably a cathepsin O comprises (more preferably consists of) UniProt Accession No. P43234 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin V” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. O60911 as described herein, or the mature form thereof. Thus, “cathepsin V” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. O60911 as described herein, or the mature form thereof. Preferably a cathepsin V comprises (more preferably consists of) UniProt Accession No. O60911 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin W” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. P56202 as described herein, or the mature form thereof. Thus, “cathepsin W” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. P56202 as described herein, or the mature form thereof. Preferably a cathepsin W comprises (more preferably consists of) UniProt Accession No. P56202 as described herein, or the mature form thereof. In the context of the invention the term “cathepsin Z” encompasses a polypeptide sequence having at least 70% sequence identity to UniProt Accession No. Q9UBR2 as described herein, or the mature form thereof. Thus, “cathepsin Z” may comprise a polypeptide sequence having at least 80% or 90% sequence identity to UniProt Accession No. Q9UBR2 as described herein, or the mature form thereof. Preferably a cathepsin Z comprises (more preferably consists of) UniProt Accession No. Q9UBR2 as described herein, or the mature form thereof. When describing endosomal cleavage sites of the invention, it is not intended that any Xaa (e.g. Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6 or Xaa7) 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 , Xaa ₆ or Xaa ₇ ) 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 cathepsin L (e.g., L1), B, D, K or S, and AEP are described herein. An engineered clostridial neurotoxin of the invention may comprise one or more of these cleavage sites. A cathepsin L (e.g., L1) cleavage site may comprise or consist of a consensus sequence selected from: preferably and/or 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 cathepsin L cleavage site may comprise or consist of a consensus sequence selected from L(LVFIY)(GKA)|(AGS)(PE)(PG)(PDE) (SEQ ID NO: 1) and/or (GM)(FVYIL)(GQT)|(GH)(PH)(HPG) (SEQ ID NO: 2), preferably L(LVFIY)(GK)|(AGS)(PE)(PG)(PDE) (SEQ ID NO: 3) and/or (GM)(FVYIL)(GQ)|(G)(PH)(HPG) (SEQ ID NO: 4); wherein 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 cathepsin B cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ L AVF GA // GLF AV GA G (SEQ ID NO: 5) and/or GLP AVFY G // FG VA G (SEQ ID NO: 6) preferably L AVF G // GLF AV G (SEQ ID NO: 7) and/or GLP AVFY G // F VA G (SEQ ID NO: 8) The amino acid residues shown at each (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 cathepsin B cleavage site may comprise or consist of a consensus sequence 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 cathepsin D cleavage site may comprise or consist of a consensus sequence selected from: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ L EL VE LF // ILF VA LE (SEQ ID NO: 9) preferably L EL V LF // ILF VA LE (SEQ ID NO: 10) 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 cathepsin D cleavage site may comprise or consist of a consensus sequence selected from L(EL)(VE)(LF)|(ILF)(VA)(LE)) (SEQ ID NO: 9), preferably L(EL)(V)(LF)|(ILF)(VA)(LE)) (SEQ ID NO: 10); wherein 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). An AEP cleavage site may comprise or consist of a consensus sequence of: P4 P3 P2 P1 // P1’ P2’ P3’ P4’ EA AG E ND // GS E LA (SEQ ID NO: 11) 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 AEP cleavage site may comprise or consist of a consensus sequence of (EA)(AG)E(ND)|(GS)E(LA) (SEQ ID NO: 11); wherein 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). An endosomal protease cleavage site of the invention may comprise or consists of one or more of: STSQKSIVAYTMSLGADSS (SEQ ID NO: 12); LFRGGHHPD (SEQ ID NO: 13); ELVTPARDFGHFGLS (SEQ ID NO: 14); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQA (SEQ ID NO: 15); STSQKSIVAYTMSLGADSSTGFGTNE (SEQ ID NO: 16); LFRGGHHPDTGFGTNE (SEQ ID NO: 17); ELVTPARDFGHFGLSTGFGTNE (SEQ ID NO: 18); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFGTNE (SEQ ID NO: 19); LFGFVG (SEQ ID NO: 20); ALVEKLLELKKK (SEQ ID NO: 21); QEAANERQQ (SEQ ID NO: 22); SGLTNIKTE (SEQ ID NO: 23); PDLKNVKSK (SEQ ID NO: 24); PGGGNKKIE (SEQ ID NO: 25); QLGKNEEGA (SEQ ID NO: 26); QKVGKAMYAP (SEQ ID NO: 27); GFLG (SEQ ID NO: 28); TVIVITLVMLKKKQ (SEQ ID NO: 29); PVETDSEEQPYLEMDL (SEQ ID NO: 30); LEGMELIVSQVHPETKENEIYPVWSGLP (SEQ ID NO: 31); QKEYALLYKLDIEP (SEQ ID NO: 32); SLAEEEVVIRSED (SEQ ID NO: 33); ERNSNLVGAA (SEQ ID NO: 34); PDLKNVKS (SEQ ID NO: 130); DLFGFVGL (SEQ ID NO: 131); GFVGLFRG (SEQ ID NO: 132); GSGLFGFVGGSG (SEQ ID NO: 133); LFGFVGLFGFVG (SEQ ID NO: 134); LFGFVGLFGFVGLFGFVG (SEQ ID NO: 135); GLFGFVGL (SEQ ID NO: 136); QAKKDFFSSHPLREPVNATED (SEQ ID NO: 137); ELVTPARD (SEQ ID NO: 138); RDFGHFGL (SEQ ID NO: 139); GLFRGHHP (SEQ ID NO: 140); GSGLFRGHHPDGSG (SEQ ID NO: 141); LFRGHHPDLFRGHHPD (SEQ ID NO: 142); ELVTPARDFGHFGLS (SEQ ID NO: 143); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFLGTNE (SEQ ID NO: 144); LFRGHHPDSTSQKSIVAYTMSLGADSS (SEQ ID NO: 145); STSQKSIVAYTMSLGADSSLFRGHHPD (SEQ ID NO: 146); STSQKSIVAYTMSLGADSSSTSQKSIVAYTMSLGADSS (SEQ ID NO: 147); LFRGHHPDLFRGHHPDLFRGHHPD (SEQ ID NO: 148); ELVTPARDFGHFGLSELVTPARDFGHFGLS (SEQ ID NO: 149); STSQKSIVAYTMSLGADSSELVTPARDFGHFGLSLFRGHHPD (SEQ ID NO: 150); QLGKNEEG (SEQ ID NO: 151); GERGFFYTPKT (SEQ ID NO: 152); GYYSTTIRYQATGFGTNE (SEQ ID NO: 171); GYYSTTIRYQATGFGTNE (SEQ ID NO: 171); LFRGHHPD (SEQ ID NO: 172); GLFRGHHPD (SEQ ID NO: 173); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFGTNEP (SEQ ID NO: 174); QAKKDFFSSHPL (SEQ ID NO: 175); REPVNATEDPSSGYYS (SEQ ID NO: 176); TTIRYQATGFGTNE (SEQ ID NO: 177); TTIRYQATGFGTNEP (SEQ ID NO: 178); EVDLLIGSS (SEQ ID NO: 179); EVDLLIGSSGE (SEQ ID NO: 180); GLAGFLGG (SEQ ID NO: 181); GLFGFVGG (SEQ ID NO: 182); TVGSFGFE (SEQ ID NO: 183); TVGSFGFEGG (SEQ ID NO: 184); LASLLELPEFLLFLQ (SEQ ID NO: 185); GLTTELFSPVD (SEQ ID NO: 186); and/or LERNSNLVGAA (SEQ ID NO: 187). An endosomal protease cleavage site of the invention may comprise or consists of one or more core Cathepsin L cleavage motif selected from MSLGADSS (SEQ ID NO: 188); LFRGHHP (SEQ ID NO: 189); GLFRGHHP (SEQ ID NO: 190); ELVTPARD (SEQ ID NO: 138); KDFFSSHP (SEQ ID NO: 191); EPVNATED (SEQ ID NO: 192); TGFGTNE (SEQ ID NO: 193); TGFGTNEP (SEQ ID NO: 194); QKVGKAMY (SEQ ID NO: 195); LLIGSS (SEQ ID NO: 196); and/or LLIGSSGE (SEQ ID NO: 197). An endosomal protease cleavage site of the invention may comprise or consists of one or more Cathepsin L cleavage site selected from: STSQKSIVAYTMSLGADSS (SEQ ID NO: 12); LFRGGHHPD (SEQ ID NO: 13); ELVTPARDFGHFGLS (SEQ ID NO: 14); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQA (SEQ ID NO: 15); STSQKSIVAYTMSLGADSS (SEQ ID NO: 16); LFRGGHHPD (SEQ ID NO: 17); ELVTPARDFGHFGLS (SEQ ID NO: 18); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFGTNE (SEQ ID NO: 19); QKVGKAMYAP (SEQ ID NO: 27); QAKKDFFSSHPLREPVNATED (SEQ ID NO: 137); ELVTPARD (SEQ ID NO: 138); RDFGHFGL (SEQ ID NO: 139); GLFRGHHP (SEQ ID NO: 140); GSGLFRGHHPDGSG (SEQ ID NO: 141); LFRGHHPDLFRGHHPD (SEQ ID NO: 142); ELVTPARDFGHFGLS (SEQ ID NO: 143); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFLGTNE (SEQ ID NO: 144); LFRGHHPDSTSQKSIVAYTMSLGADSS (SEQ ID NO: 145); STSQKSIVAYTMSLGADSSLFRGHHPD (SEQ ID NO: 146); STSQKSIVAYTMSLGADSSSTSQKSIVAYTMSLGADSS (SEQ ID NO: 147); LFRGHHPDLFRGHHPDLFRGHHPD (SEQ ID NO: 148); ELVTPARDFGHFGLSELVTPARDFGHFGLS (SEQ ID NO: 149); STSQKSIVAYTMSLGADSSELVTPARDFGHFGLSLFRGHHPD (SEQ ID NO: 150); GYYSTTIRYQATGFGTNE (SEQ ID NO: 171); LFRGHHPD (SEQ ID NO: 172); GLFRGHHPD (SEQ ID NO: 173); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFGTNEP (SEQ ID NO: 174); QAKKDFFSSHPL (SEQ ID NO: 175); REPVNATEDPSSGYYS (SEQ ID NO: 176); TTIRYQATGFGTNE (SEQ ID NO: 177); TTIRYQATGFGTNEP (SEQ ID NO: 178); EVDLLIGSS (SEQ ID NO: 179); and/or EVDLLIGSSGE (SEQ ID NO: 180). An endosomal protease cleavage site of the invention may comprise or consists of one or more core Cathepsin B cleavage motif selected from LFGFVF (SEQ ID NO: 20); GLAGFLGG (SEQ ID NO: 181); GLFGFVGG (SEQ ID NO: 182); GSFGFE (SEQ ID NO: 198); and/or GSFGFEGG (SEQ ID NO: 199). An endosomal protease cleavage site of the invention may comprise or consists of one or more Cathepsin B cleavage site selected from: LFGFVG (SEQ ID NO: 20); GFLG (SEQ ID NO: 28); DLFGFVGL (SEQ ID NO: 131); GFVGLFRG (SEQ ID NO: 132); GSGLFGFVGGSG (SEQ ID NO: 133); LFGFVGLFGFVG (SEQ ID NO: 134); LFGFVGLFGFVGLFGFVG (SEQ ID NO: 135); GLFGFVGL (SEQ ID NO: 136); GLAGFLGG (SEQ ID NO: 181); GLFGFVGG (SEQ ID NO: 182); TVGSFGFE (SEQ ID NO: 183); and/or TVGSFGFEGG (SEQ ID NO: 184). An endosomal protease cleavage site of the invention may comprise or consists of one or more core Cathepsin D cleavage motif selected from VEKLLELK (SEQ ID NO: 200); VITLVMLK (SEQ ID NO: 201); GMELIVSQ (SEQ ID NO: 202); QPYLEMDL (SEQ ID NO: 203); EYALLYKL (SEQ ID NO: 204); LAEEEVVI (SEQ ID NO: 205); LASLLELP (SEQ ID NO: 206); and/or TTELFSPV (SEQ ID NO: 207). An endosomal protease cleavage site of the invention may comprise or consists of one or more Cathepsin D cleavage site selected from: ALVEKLLELKKK (SEQ ID NO: 21); TVIVITLVMLKKKQ (SEQ ID NO: 29); PVETDSEEQPYLEMDL (SEQ ID NO: 30); LEGMELIVSQVHPETKENEIYPVWSGLP (SEQ ID NO: 31); QKEYALLYKLDIEP (SEQ ID NO: 32); SLAEEEVVIRSED (SEQ ID NO: 33); GERGFFYTPKT (SEQ ID NO: 152); LASLLELPEFLLFLQ (SEQ ID NO: 185); and/or GLTTELFSPVD (SEQ ID NO: 186). An endosomal protease cleavage site of the invention may comprise or consists of one or more core AEP cleavage motif selected from EAANERQQ (SEQ ID NO: 208); GLTNIKTE (SEQ ID NO: 209); DLKNVKSK (SEQ ID NO: 210); GGGNKKIE (SEQ ID NO: 211); LGKNEEGA (SEQ ID NO: 212); ERNSNLV (SEQ ID NO: 213); and/or LERNSNLV (SEQ ID NO: 214). An endosomal protease cleavage site of the invention may comprise or consists of one or more AEP cleavage site selected from: QEAANERQQ (SEQ ID NO: 22); SGLTNIKTE (SEQ ID NO: 23); PDLKNVKSK (SEQ ID NO: 24); PGGGNKKIE (SEQ ID NO: 25); QLGKNEEGA (SEQ ID NO: 26); ERNSNLVGAA (SEQ ID NO: 34); PDLKNVKS (SEQ ID NO: 130); QLGKNEEG (SEQ ID NO: 151); and/or LERNSNLVGAA (SEQ ID NO: 187). An engineered clostridial neurotoxin of the invention may comprise one or more endosomal protease cleavage site as defined herein. In some embodiments an endosomal protease cleavage site of the invention has at least 70% sequence identity to any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187.An endosomal protease cleavage site may have at least 80%, 85% or 90% sequence identity to any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187. Preferably an endosomal protease cleavage site has at least 95% sequence identity to any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187. More preferably, an endosomal protease cleavage site has at least 99% sequence identity to any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187. Particularly preferred is an endosomal protease cleavage site comprising or consisting of any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171- 187; or 12 to 34, 130-152 or 171-187. Typically said endosomal protease cleavage site comprises or consists of one or more of the amino acid sequence of any one of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187, or the exogenous activation loop comprises said one or more endosomal protease cleavage site. As described herein, one or more endosomal protease cleavage site may be comprised in an exogenous activation loop together with one or more spacer sequence as defined herein. Spacer sequences may typically be present when the one or more endosomal 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 endosomal protease cleavage sites. Preferably, a spacer may be a GS spacer as defined herein. An engineered clostridial neurotoxin of the invention may comprise one or more endosomal protease cleavage site. In other words, an engineered clostridial neurotoxin of the invention may comprise one endosomal protease cleavage site as described herein, or multiple endosomal protease cleavage sites. An engineered clostridial neurotoxin of the invention may comprise two, three, four, five, six, seven, eight, nine, ten or more endosomal 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) endosomal protease cleavage site. When an engineered clostridial neurotoxin of the invention comprises multiple endosomal protease cleavage sites, these may each be selected independently. Typically, when an engineered clostridial neurotoxin of the invention comprises multiple endosomal protease cleavage sites, each endosomal protease cleavage site may independently be selected from the endosomal protease cleavage sites described herein. Thus, an engineered clostridial neurotoxin of the invention may comprise multiple endosomal 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 endosomal protease cleavage sites, or any combination thereof. Whether an exogenous activation loop comprises multiple different endosomal protease cleavage sites or multiple copies of the same endosomal protease cleavage site, said cleavage sites may be directly linked, or may be separated by one or more spacer as described herein. Multiple endosomal protease cleavage sites may be introduced at a single location within a clostridial neurotoxin. Alternatively, multiple endosomal protease cleavage sites may be introduced at multiple locations within a clostridial neurotoxin. By way of non-limiting example, one endosomal protease cleavage site may be introduced within the activation loop within a clostridial neurotoxin and another (same or different) endosomal protease cleavage site may be introduced within the LHN domain. Typically, where multiple endosomal 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 endosomal protease cleavage sites are introduced into an engineered clostridial neurotoxin according to the invention, they are each introduced within the activation loop of the clostridial neurotoxin. The relative positioning of individual endosomal protease cleavage sites within an exogenous activation loop of the invention may be determined by the structure-function relationship for the endosomal protease in question. It is within the routine practice of one of ordinary skill in the art to appropriately position individual endosomal protease cleavage sites within an exogenous activation loop comprising multiple endosomal protease cleavage site based on this structure-function relationship, without undue burden. Examples of polypeptide sequences comprising multiple endosomal protease cleavage sites are: ALVEKLLELKKKELVTPARDFGHFGLS (SEQ ID NO: 35); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQA (SEQ ID NO: 36); STSQKSIVAYTMSLGADSSGLFGFVGLFRGHHPD (SEQ ID NO: 37); or QEAANERQQSGLTNIKTEPDLKNVKSKPGGGNKKIEQLGKNEEGA (SEQ ID NO: 38). The bold and underlined residues identify P1 residues within endosomal protease cleavage sites, i.e., the sites after which peptide bond hydrolysis occurs. Thus, it can be seen that ALVEKLLELKKKELVTPARDFGHFGLS (SEQ ID NO: 35) comprises three endosomal protease cleavage sites (two for cathepsin L and one for cathepsin D); QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQA (SEQ ID NO: 36) comprises two cathepsin L cleavage sites; STSQKSIVAYTMSLGADSSGLFGFVGLFRGHHPD (SEQ ID NO: 37) comprises three endosomal protease cleavage sites (two for cathepsin L and one for cathepsin B); and QEAANERQQSGLTNIKTEPDLKNVKSKPGGGNKKIEQLGKNEEGA (SEQ ID NO: 38) comprises five different AEP cleavage sites. Accordingly, an engineered clostridial neurotoxin of the invention may comprise one or more of SEQ ID NOs: 35 to 38. An exogenous activation loop comprising one or more endosomal protease cleavage site may be any length, provided that the architecture of the exogenous activation loop, and typically the clostridial neurotoxin, is preserved and cleavage at the one or more endosomal protease activation loop results in the formation of an active di-chain form of the engineered clostridial neurotoxin. The exogenous 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 which are 17 amino acids in length, as such exogenous 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. An exemplary reference BoNT/A sequence is the BoNT/A1 sequence shown as SEQ ID NO: 45 or 117. Other non-limiting examples of BoNT/A sequences include those of SEQ ID NOs: 46 to 52. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/B. An exemplary reference BoNT/B sequence is the BoNT/B1 sequence shown as SEQ ID NO: 53. Other non- limiting examples of BoNT/B sequences include those of SEQ ID NOs: 54 to 60. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/C. An exemplary reference BoNT/C1 sequence is shown as SEQ ID NO: 61. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/D. An exemplary reference BoNT/D sequence is shown as SEQ ID NO: 62. The clostridial neurotoxin (e.g., pre-engineering) may be a BoNT/CD chimera. An exemplary reference BoNT/CD sequence is shown as SEQ ID NO: 63. The clostridial neurotoxin (e.g., pre-engineering) may be a BoNT/DC chimera. An exemplary reference BoNT/DC sequence is shown as SEQ ID NO: 64. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/E. An exemplary reference BoNT/E sequence is shown as SEQ ID NO: 65. Other non-limiting examples of BoNT/E sequences include those of SEQ ID NOs: 66 to 77. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/F. An exemplary reference BoNT/F sequence is the BoNT/F1 sequence shown as SEQ ID NO: 78. Other non- limiting examples of BoNT/F sequences include those of SEQ ID NOs: 79 to 84. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/G. An exemplary reference BoNT/G sequence is shown as SEQ ID NO: 85. The clostridial neurotoxin (e.g., pre-engineering) may be a BoNT/FA chimera. An exemplary reference BoNT/FA sequence is shown as SEQ ID NO: 86. The clostridial neurotoxin (e.g., pre-engineering) may be BoNT/X. An exemplary reference BoNT/X sequence is shown as SEQ ID NO: 87. The clostridial neurotoxin (e.g., pre-engineering) may be TeNT. An exemplary reference TeNT sequence is shown as SEQ ID NO: 88. 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 HC domain) and an N-terminal translocation component (HN 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 C ₁ 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: 113), 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 (eg. 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 H _N domain (or a functional component thereof). H _N 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 HC 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 HN 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 HN 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 HN 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 HN 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 spike 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 H _C 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 HC 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 HC domain of an engineered clostridial neurotoxin of the invention is a BoNT/X HC 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 (e.g. influenza A virus fusogenic peptide domain of 23 amino acids), alphavirus fusogenic peptide domain (e.g. Semliki Forest virus fusogenic peptide domain of 26 amino acids), vesiculovirus fusogenic peptide domain (e.g. vesicular stomatitis virus fusogenic peptide domain of 21 amino acids), respirovirus fusogenic peptide domain (e.g. Sendai virus fusogenic peptide domain of 25 amino acids), morbiliivirus fusogenic peptide domain (e.g. Canine distemper virus fusogenic peptide domain of 25 amino acids), avulavirus fusogenic peptide domain (e.g. Newcastle disease virus fusogenic peptide domain of 25 amino acids), henipavirus fusogenic peptide domain (e.g. Hendra virus fusogenic peptide domain of 25 amino acids), metapneumovirus fusogenic peptide domain (e.g. 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 HCN 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 HCN 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 H _CN translocation facilitating domain may be combined with a non-clostridial translocation domain peptide. Alternatively, a clostridial neurotoxin H _CN 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 HC domain of a clostridial neurotoxin. Accordingly, said clostridial neurotoxins are not able to bind rat synaptosomal membranes (via a clostridial HC 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 HC 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 H _C 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 H _C 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 H _CN peptide or domain) and the C-terminal region (commonly referred to as the H _CC 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 HC 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 HCC peptide. In other words, the HCC 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 HN peptide of the present invention may be C-terminally extended, i.e. it may be associated with all or part of a clostridial neurotoxin HC domain, e.g. the HCN, HCC or HC domain. References herein to a clostridial neurotoxin HN peptide of the present invention encompass such C-terminally extended HN peptides, which comprise one or more amino acid residues from a clostridial neurotoxin HC domain. Alternatively, a clostridial neurotoxin HN peptide of the present invention may not be associated with (or lack) all or part of a clostridial neurotoxin HC domain, e.g. the HCN, HCC or HC domain. Typically if a clostridial neurotoxin of the invention or a clostridial neurotoxin HN peptide of the present invention lacks all or part of a C-terminal peptide portion (HCC) of a clostridial neurotoxin it thus lacks the HC binding function of native clostridial neurotoxin. By way of example, a C-terminally extended clostridial H _N 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 H _N peptide of the present invention may lack the entire C-terminal peptide portion (H _CC ) of a clostridial neurotoxin and thus lacks the H _C binding function of native clostridial neurotoxin. By way of example, the clostridial H _N 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 H _N peptide of the present invention lacks a clostridial H _CC 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/A1. 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 HC 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 HC domain can include modifying residues in the ganglioside binding site of the HC 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 H _C domain further comprises at least one amino acid residue substitution, insertion, indel or deletion in the H _CC 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 H _CC 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 H _CC 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 H _CC 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 HCC 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 HCC 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: 118. E1191M may correspond to position 1204 of SEQ ID NO: 118 and S1199Y may correspond to position 1212. Thus, SEQ ID NO: 118 may comprise 1204M and 1212Y. The modification may be a modification when compared to unmodified BoNT/B shown as SEQ ID NO: 53, wherein the amino acid residue numbering is determined by alignment with SEQ ID NO: 53. As the presence of a methionine residue at position 1 of SEQ ID NO: 53 (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: 53 includes a methionine, the position numbering will be as defined above (e.g. E1191 will be E1191 of SEQ ID NO: 53). Alternatively, where the methionine is absent from SEQ ID NO: 53 the amino acid residue numbering should be modified by -1 (e.g. E1191 will be E1190 of SEQ ID NO: 53). 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, xExxxLL, xExxxIL, and xExxxLM (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, HN, HCN and HCC (as defined herein). For example, the (pre-engineering) LHN/A1-HCB1 chimera of SEQ ID NO: 118 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 endosomal protease cleavage site) may comprise: i. A BoNT/A L-chain and a non-BoNT/A H _N and H _C domain; ii. A BoNT/A H _N domain and a non-BoNT/A L-chain and H _C domain iii. A BoNT/A H _C domain and a non-BoNT/A L-chain and H _N domain; iv. A BoNT/A L-chain and H _N domain and a non-BoNT/A H _C domain v. A BoNT/A L-chain and H _C domain and a non-BoNT/A H _N domain; or vi. A BoNT/A H _N domain and H _C 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 HN domain and a BoNT/B HC domain (such as LHN/A1-HC/B1). An exemplary non-engineered LHN/A1-HCB1 chimera that may be modified to comprises one or more endosomal protease cleavage site according to the invention is given in SEQ ID NO: 118. An exemplary engineered form of the LHN/A1-HCB1 chimera of SEQ ID NO: 118 is given in SEQ ID NO: 159. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a BoNT/C1 HC domain. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a BoNT/D HC domain. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a BoNT/E HC domain. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a BoNT/F HC domain. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a BoNT/G HC domain. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a BoNT/X HC domain. A clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin) may comprise a BoNT/A L-chain and HN domain and a TeNT HC domain. For example, a clostridial neurotoxin of the invention (e.g., an engineered clostridial neurotoxin comprising one or more endosomal protease cleavage site) may comprise: i. A BoNT/B L-chain and a non-BoNT/B H _N and H _C domain; ii. A BoNT/B H _N domain and a non-BoNT/B L-chain and H _C domain iii. A BoNT/B H _C domain and a non-BoNT/B L-chain and H _N domain; iv. A BoNT/B L-chain and H _N domain and a non-BoNT/B H _C domain v. A BoNT/B L-chain and H _C domain and a non-BoNT/B H _N domain; or vi. A BoNT/B H _N domain and H _C 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 endosomal protease cleavage site) may comprise: i. A BoNT/C1 L-chain and a non-BoNT/C1 H _N and H _C domain; ii. A BoNT/C1 H _N domain and a non-BoNT/C1 L-chain and H _C domain iii. A BoNT/C1 H _C domain and a non-BoNT/C1 L-chain and H _N domain; iv. A BoNT/C1 L-chain and H _N domain and a non-BoNT/C1 H _C domain v. A BoNT/C1 L-chain and H _C domain and a non-BoNT/C1 H _N domain; or vi. A BoNT/C1 H _N domain and H _C 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 endosomal protease cleavage site) may comprise: i. A BoNT/D L-chain and a non-BoNT/D HN and HC domain; ii. A BoNT/D HN domain and a non-BoNT/D L-chain and HC domain iii. A BoNT/D HC domain and a non-BoNT/D L-chain and HN domain; iv. A BoNT/D L-chain and HN domain and a non-BoNT/D HC domain v. A BoNT/D L-chain and HC domain and a non-BoNT/D HN domain; or vi. A BoNT/D HN domain and HC 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 endosomal protease cleavage site) may comprise: i. A BoNT/E L-chain and a non-BoNT/E HN and HC domain; ii. A BoNT/E HN domain and a non-BoNT/E L-chain and HC domain iii. A BoNT/E HC domain and a non-BoNT/E L-chain and HN domain; iv. A BoNT/E L-chain and HN domain and a non-BoNT/E HC domain v. A BoNT/E L-chain and HC domain and a non-BoNT/E HN domain; or vi. A BoNT/E HN domain and HC 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 endosomal protease cleavage site) may comprise: i. A BoNT/F L-chain and a non-BoNT/F HN and HC domain; ii. A BoNT/F H _N domain and a non-BoNT/F L-chain and H _C domain iii. A BoNT/F H _C domain and a non-BoNT/F L-chain and H _N domain; iv. A BoNT/F L-chain and H _N domain and a non-BoNT/F H _C domain v. A BoNT/F L-chain and H _C domain and a non-BoNT/F H _N domain; or vi. A BoNT/F H _N domain and H _C 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 endosomal protease cleavage site) may comprise: i. A BoNT/G L-chain and a non-BoNT/G H _N and H _C domain; ii. A BoNT/G H _N domain and a non-BoNT/G L-chain and H _C domain iii. A BoNT/G H _C domain and a non-BoNT/G L-chain and H _N domain; iv. A BoNT/G L-chain and H _N domain and a non-BoNT/G H _C domain v. A BoNT/G L-chain and H _C domain and a non-BoNT/G H _N domain; or vi. A BoNT/G H _N domain and H _C 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 endosomal protease cleavage site) may comprise: i. A BoNT/X L-chain and a non-BoNT/X H _N and H _C domain; ii. A BoNT/X H _N domain and a non-BoNT/X L-chain and H _C domain iii. A BoNT/X HC domain and a non-BoNT/X L-chain and HN domain; iv. A BoNT/X L-chain and HN domain and a non-BoNT/X HC domain v. A BoNT/X L-chain and HC domain and a non-BoNT/X HN domain; or vi. A BoNT/X HN domain and HC 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 endosomal protease cleavage site) may comprise: i. A TeNT L-chain and a non-TeNT HN and HC domain; ii. A TeNT HN domain and a non-TeNT L-chain and HC domain iii. A TeNT HC domain and a non-TeNT L-chain and HN domain; iv. A TeNT L-chain and HN domain and a non-TeNT HC domain v. A TeNT L-chain and HC domain and a non-TeNT HN domain; or vi. A TeNT HN domain and HC 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 H _C domain, or the H _CC 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 endosomal 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 (HN/A), particularly preferred both a LC/A and HN/A. In some 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. Such engineered re-targeted BoNT/X are particularly preferred. Non-limiting examples of engineered re-targeted clostridial neurotoxins include those of SEQ ID NOs: 121, 160, 161 and 162. 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 H _C 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. Non-native protease cleavage sites that may be employed in clostridial neurotoxins include: TEV(Tobacco Etch virus) (ENLYFQ↓G) (SEQ ID NO: 114) Thrombin (LVPR↓GS) (SEQ ID NO: 115) PreScission (LEVLFQ↓GP) (SEQ ID NO: 116). 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 off-target and/or adverse 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). Tolerance may be quantified/determined as described below. 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. 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 endosomal protease cleavage site as described herein. The nucleotide sequence may comprise a sequence having at least 70% sequence identity to SEQ ID NO: 163, and wherein the nucleic acid encoding the BoNT/C activation loop (SEQ ID NO: 164) is replaced by a nucleic acid encoding the one or more endosomal protease site or the exogenous activation loop comprising said one or more endosomal cleavage sites. The nucleotide sequence may comprise a sequence having at least 80% or 90% sequence identity to SEQ ID NO: 163, wherein the nucleic acid encoding the BoNT/C activation loop (SEQ ID NO: 164) is replaced by a nucleic acid encoding the one or more endosomal protease site or the exogenous activation loop comprising said one or more endosomal cleavage sites. Preferably the nucleotide sequence comprises (more preferably consists of) SEQ ID NO: 163, wherein the nucleic acid encoding the BoNT/C activation loop (SEQ ID NO: 164) is replaced by a nucleic acid encoding the one or more endosomal protease site or the exogenous activation loop comprising said one or more endosomal cleavage sites. Non-limiting examples of nucleic acids encoding exogenous activation loops which may replace SEQ ID NO: 164 within SEQ ID NO: 163 include SEQ ID NOs: 165, 166 and 167. Thus, non-limiting examples of nucleic acids encoding exemplary engineered clostridial neurotoxins (particularly engineered re-targeted BoNT/X) include SEQ ID NOs: 168, 169 and 170. The nucleotide sequence may encode an engineered clostridial neurotoxin having at least 70% sequence identity to one or more of SEQ ID NOs: 121 or 159-162. The nucleotide sequence may encode an engineered clostridial neurotoxin having at least 80% or 90% sequence identity to one or more of SEQ ID NOs: 121 or 159-162. Preferably the nucleotide sequence encode an engineered clostridial neurotoxin comprising (more preferably consisting of) any one of SEQ ID NOs: 121 or 159-162. 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 endosomal 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 endosomal protease, thereby producing a di-chain clostridial neurotoxin. Said contacting may be in vitro, ex vivo, or in vivo, preferably in vivo. As such, 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 endosomal protease activation site by one or more endosomal protease expression within target cells. Thus, a method of the invention may further comprise contacting an engineered clostridial neurotoxin with one or more endosomal protease thereby producing a corresponding di-chain engineered clostridial neurotoxin. Preferably said contacting occurs in vivo. 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 endosomal protease; wherein the single-chain clostridial neurotoxin has an activation loop comprising or consisting of one or more endosomal protease cleavage site as described herein (e.g. any one or more of SEQ ID NOs: 1 to 38, 130-152 or 171-187; 12 to 38, 130-152 or 171-187; 1 to 34, 130-152 or 171-187; or 12 to 34, 130-152 or 171-187; and wherein one or more endosomal protease hydrolyses a peptide bond of the activation loop thereby producing a di-chain clostridial neurotoxin. Preferably said contacting occurs in vivo. The present invention encompasses contacting a single-chain clostridial neurotoxin (e.g., an engineered clostridial neurotoxin of the invention) with one or more endosomal protease, wherein one or more endosomal 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 vivo. 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 endosomal 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 endosomal 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 endosomal 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 endosomal 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 endosomal 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 endosomal 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 endosomal proteases. Exemplary endosomal 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 endosomal 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 2µg to about 5µg of cathepsin L may be used per 0.1- 1mg of engineered clostridial neurotoxin, with activation carried out at room temperature (about 21°C) for 1-3 hours. By way of a further non-limiting example, between about 10µg to about 25µg of AEP may be used per 0.1-1mg of engineered clostridial neurotoxin, with activation carried out at room temperature (about 21°C) for 1-3 hours. Other temperatures may be used (e.g. about 4°C or about 37°C), with corresponding increases/decreases respectively in the amount of endosomal protease. Many cells endogenously express one or more endosomal proteases, within endosomes and/or lysosomes. As used herein, the term endosome encompasses lysosomes. Thus, the one or more endosomal protease expressed by cells is typically present within the cell. Therefore, the step of contacting a clostridial neurotoxin with one or more endosomal protease according to the invention may occur within a cell treated with the clostridial neurotoxin. In other words, contacting a clostridial neurotoxin with one or more endosomal protease according to the invention may involve one or more endosomal protease endogenously present within target cells. Accordingly, contacting a clostridial neurotoxin with one or more endosomal 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 endosomal protease endogenously present within one or more cells present in a tissue or organ to be treated according to the invention. 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 endosomal 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. 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 endosomal protease as described herein, the clostridial neurotoxin is preferably in a single-chain form for administration. Alternatively, the engineered clostridial neurotoxin of the invention may be 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 an (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 endosomal 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 single-chain form (e.g. engineered to comprise one or more endosomal protease cleavage site). 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 – cathepsin L cleavage site consensus sequence Leu Xaa ₁ Xaa ₂ Xaa ₃ Xaa ₄ Xaa ₅ Xaa ₆ where: Xaa ₁ Xaa ₂ being preferred) Xaa3 Xaa ₄ Xaa5 Xaa ₆ SEQ ID NO: 2 – cathepsin L cleavage site consensus sequence Xaa ₁ Xaa ₂ Xaa ₃ Xaa ₄ Xaa ₅ Xaa ₆ where: Xaa ₁ Xaa2 Xaa ₃ or Q being preferred) Xaa4 being preferred) Xaa ₅ Xaa6 SEQ ID NO: 3 – cathepsin L cleavage site consensus sequence Leu Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 where: Xaa1 Xaa ₂ Xaa3 Xaa ₄ Xaa5 Xaa ₆ SEQ ID NO: 4 – cathepsin L cleavage site consensus sequence Xaa ₁ Xaa ₂ Xaa ₃ Gly Xaa ₄ Xaa ₅ where: Xaa ₁ Xaa2 Xaa ₃ Xaa4 Xaa ₅ SEQ ID NO: 5 – cathepsin B cleavage site consensus sequence Leu Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Gly where: Xaa ₁ is A, V or F Xaa ₂ is G or A (G being preferred) Xaa ₃ is G, L or F Xaa4 is A or V Xaa ₅ is G or A (G being preferred) SEQ ID NO: 6 – cathepsin B cleavage site consensus sequence Xaa1 Xaa2 Gly Xaa3 Xaa4 Gly where: Xaa ₁ is G, L or P Xaa2 is A, V, F or Y Xaa ₃ is F or G (F being preferred) Xaa4 is V or A SEQ ID NO: 7 – cathepsin B cleavage site consensus sequence Leu Xaa ₁ Gly Xaa ₂ Xaa ₃ Gly Gly where: Xaa1 is A, V or F Xaa2 is G, L or F Xaa3 is A or V SEQ ID NO: 8 – cathepsin B cleavage site consensus sequence Xaa ₁ Xaa ₂ Gly Phe Xaa ₃ Gly where: Xaa ₁ is G, L or P Xaa2 is A, V, F or Y Xaa ₃ is V or A SEQ ID NO: 9 – cathepsin D cleavage site consensus sequence Leu Xaa ₁ Xaa ₂ Xaa ₃ Xaa ₄ Xaa ₅ Xaa ₆ where: Xaa ₁ is E or L Xaa2 is V or E (V being preferred) Xaa ₃ is L or F Xaa4 is I, L or F Xaa5 is V or A Xaa ₆ is L or E SEQ ID NO: 10 – cathepsin D cleavage site consensus sequence Leu Xaa ₁ Val Xaa ₂ Xaa ₃ Xaa ₄ Xaa ₅ where: Xaa1 is E or L Xaa ₂ is L or F Xaa3 is I, L or F Xaa ₄ is V or A Xaa5 is L or E SEQ ID NO: 11 – AEP cleavage site consensus sequence Xaa1 Xaa2 Glu Xaa3 Xaa4 Glu Xaa5 where: Xaa1 is E or A Xaa ₂ is A or G Xaa3 is N or D Xaa ₄ is G or S Xaa5 is L or A SEQ ID NO: 12 – Cathepsin L cleavage site STSQKSIVAYTMSLGADSS SEQ ID NO: 13 – Cathepsin L cleavage site LFRGGHHPD SEQ ID NO: 14 – Cathepsin L cleavage site ELVTPARDFGHFGLS SEQ ID NO: 15 – Cathepsin L cleavage site QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQA SEQ ID NO: 16 – Cathepsin L cleavage site STSQKSIVAYTMSLGADSSTGFGTNE SEQ ID NO: 17 – Cathepsin L cleavage site LFRGGHHPDTGFGTNE SEQ ID NO: 18 – Cathepsin L cleavage site ELVTPARDFGHFGLSTGFGTNE SEQ ID NO: 19 – Cathepsin L cleavage site QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFGTNE SEQ ID NO: 20 – Cathepsin B cleavage site LFGFVG SEQ ID NO: 21 – Cathepsin D cleavage site ALVEKLLELKKK SEQ ID NO: 22 – AEP cleavage site QEAANERQQ SEQ ID NO: 23 – AEP cleavage site SGLTNIKTE SEQ ID NO: 24 – AEP cleavage site PDLKNVKSK SEQ ID NO: 25 – AEP cleavage site PGGGNKKIE SEQ ID NO: 26 – AEP cleavage site QLGKNEEGA SEQ ID NO: 27 – Cathepsin L cleavage site QKVGKAMYAP SEQ ID NO: 28 – Cathepsin B cleavage site GFLG SEQ ID NO: 29 – Cathepsin D cleavage site TVIVITLVMLKKKQ SEQ ID NO: 30 – Cathepsin D cleavage site PVETDSEEQPYLEMDL SEQ ID NO: 31 – Cathepsin D cleavage site LEGMELIVSQVHPETKENEIYPVWSGLP SEQ ID NO: 32 – Cathepsin D cleavage site QKEYALLYKLDIEP SEQ ID NO: 33 – Cathepsin D cleavage site SLAEEEVVIRSED SEQ ID NO: 34 – AEP cleavage site ERNSNLVGAA SEQ ID NO: 35 – multiple endosomal protease cleavage site ALVEKLLELKKKELVTPARDFGHFGLS The bold and underlined residues identify P1 residues within endosomal protease cleavage sites SEQ ID NO: 36 – multiple endosomal protease cleavage site QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQA The bold and underlined residues identify P1 residues within endosomal protease cleavage sites SEQ ID NO: 37 – multiple endosomal protease cleavage site STSQKSIVAYTMSLGADSSGLFGFVGLFRGHHPD The bold and underlined residues identify P1 residues within endosomal protease cleavage sites SEQ ID NO: 38 – multiple endosomal protease cleavage site QEAANERQQSGLTNIKTEPDLKNVKSKPGGGNKKIEQLGKNEEGA SEQ ID NO: 39 – human cathepsin L1 amino acid sequence (UniProt Accession No. P07711) MNPTLILAAFCLGIASATLTFDHSLEAQWTKWKAMHNRLYGMNEEGWRRAVWEKNMKMIE LHNQEYREGKHSFTMAMNAFGDMTSEEFRQVMNGFQNRKPRKGKVFQEPLFYEAPRSVD WREKGYVTPVKNQGQCGSCWAFSATGALEGQMFRKTGRLISLSEQNLVDCSGPQGNEG CNGGLMDYAFQYVQDNGGLDSEESYPYEATEESCKYNPKYSVANDTGFVDIPKQEKALMK AVATVGPISVAIDAGHESFLFYKEGIYFEPDCSSEDMDHGVLVVGYGFESTESDNNKYWL V KNSWGEEWGMGGYVKMAKDRRNHCGIASAASYPTV SEQ ID NO: 40 – human cathepsin B amino acid sequence (UniProt Accession No. P07858) MWQLWASLCCLLVLANARSRPSFHPLSDELVNYVNKRNTTWQAGHNFYNVDMSYLKRLC GTFLGGPKPPQRVMFTEDLKLPASFDAREQWPQCPTIKEIRDQGSCGSCWAFGAVEAISD RICIHTNAHVSVEVSAEDLLTCCGSMCGDGCNGGYPAEAWNFWTRKGLVSGGLYESHVG CRPYSIPPCEHHVNGSRPPCTGEGDTPKCSKICEPGYSPTYKQDKHYGYNSYSVSNSEKD I MAEIYKNGPVEGAFSVYSDFLLYKSGVYQHVTGEMMGGHAIRILGWGVENGTPYWLVANS WNTDWGDNGFFKILRGQDHCGIESEVVAGIPRTDQYWEKI SEQ ID NO: 41 – human cathepsin D amino acid sequence (UniProt Accession No. P07339) MQPSSLLPLALCLLAAPASALVRIPLHKFTSIRRTMSEVGGSVEDLIAKGPVSKYSQAVP AVT EGPIPEVLKNYMDAQYYGEIGIGTPPQCFTVVFDTGSSNLWVPSIHCKLLDIACWIHHKY NS DKSSTYVKNGTSFDIHYGSGSLSGYLSQDTVSVPCQSASSASALGGVKVERQVFGEATKQ PGITFIAAKFDGILGMAYPRISVNNVLPVFDNLMQQKLVDQNIFSFYLSRDPDAQPGGEL ML GGTDSKYYKGSLSYLNVTRKAYWQVHLDQVEVASGLTLCKEGCEAIVDTGTSLMVGPVDE VRELQKAIGAVPLIQGEYMIPCEKVSTLPAITLKLGGKGYKLSPEDYTLKVSQAGKTLCL SGF MGMDIPPPSGPLWILGDVFIGRYYTVFDRDNNRVGFAEAARL SEQ ID NO: 42 – human cathepsin K amino acid sequence (UniProt Accession No. P43235) MWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIH NLE ASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVDYRK KGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGGY MTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVAR VGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGEN W GNKGYILMARNKNNACGIANLASFPKM SEQ ID NO: 43 – human cathepsin S amino acid sequence (UniProt Accession No. P25774) MKRLVCVLLVCSSAVAQLHKDPTLDHHWHLWKKTYGKQYKEKNEEAVRRLIWEKNLKFVM LHNLEHSMGMHSYDLGMNHLGDMTSEEVMSLMSSLRVPSQWQRNITYKSNPNRILPDSV DWREKGCVTEVKYQGSCGACWAFSAVGALEAQLKLKTGKLVSLSAQNLVDCSTEKYGNK GCNGGFMTTAFQYIIDNKGIDSDASYPYKAMDQKCQYDSKYRAATCSKYTELPYGREDVL K EAVANKGPVSVGVDARHPSFFLYRSGVYYEPSCTQNVNHGVLVVGYGDLNGKEYWLVKN SWGHNFGEEGYIRMARNKGNHCGIASFPSYPEI SEQ ID NO: 44 – human AEP amino acid sequence (UniProt Accession No. Q99538) MVWKVAVFLSVALGIGAVPIDDPEDGGKHWVVIVAGSNGWYNYRHQADACHAYQIIHRNG I PDEQIVVMMYDDIAYSEDNPTPGIVINRPNGTDVYQGVPKDYTGEDVTPQNFLAVLRGDA E AVKGIGSGKVLKSGPQDHVFIYFTDHGSTGILVFPNEDLHVKDLNETIHYMYKHKMYRKM VF YIEACESGSMMNHLPDNINVYATTAANPRESSYACYYDEKRSTYLGDWYSVNWMEDSDVE DLTKETLHKQYHLVKSHTNTSHVMQYGNKTISTMKVMQFQGMKRKASSPVPLPPVTHLDL T PSPDVPLTIMKRKLMNTNDLEESRQLTEEIQRHLDARHLIEKSVRKIVSLLAASEAEVEQ LLS ERAPLTGHSCYPEALLHFRTHCFNWHSPTYEYALRHLYVLVNLCEKPYPLHRIKLSMDHV C LGHY SEQ ID NO: 45 (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: 117. The endogenous activation loop is dash-underlined. SEQ ID NO: 46 (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: 47 (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: 48 (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: 49 (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: 50 (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: 51 (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: 52 (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: 53 (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: 54 (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: 55 (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: 56 (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: 57 (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: 58 (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: 59 (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: 60 (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: 61 (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: 62 (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: 63 (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: 64 (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: 65 (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: 66 (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: 67 (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: 68 (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: 69 (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: 70 (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: 71 (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: 72 (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: 73 (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: 74 (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: 75 (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: 76 (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: 77 (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: 78 (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: 79 (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: 80 (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: 81 (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: 82 (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: 83 (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: 84 (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: 85 (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: 86 (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: 87 (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: 88 (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: 89 (BoNT/D Activation Loop) CLRLTKNSRDDSTC SEQ ID NO: 90 (BoNT/DC Activation Loop) CLRLTRNSRDDSTC SEQ ID NO: 91 (BoNT/C1 and CD Activation Loop) CHKAIDGRSLYNKTLDC SEQ ID NO: 92 (BoNT/A4 Activation Loop) CVRGIITSKTKSLDEGYNKALNELC SEQ ID NO: 93 (BoNT/A5 and A7 Activation Loop) CVRGIITSKTKSLDEGYNKALNDLC SEQ ID NO: 94 (BoNT/A1 and A6 Activation Loop) CVRGIITSKTKSLDKGYNKALNDLC SEQ ID NO: 95 (BoNT/A3 Activation Loop) CVRGIIPFKTKSLDEGYNKALNYLC SEQ ID NO: 96 (BoNT/A2 and A8 Activation Loop) CVRGIIPFKTKSLDEGYNKALNDLC SEQ ID NO: 97 (BoNT/H Activation Loop) CSNSNTKNSLC SEQ ID NO: 98 (BoNT/E1 to E5, E9 and E12 Activation Loop) CKNIVSVKGIRKSIC SEQ ID NO: 99 (BoNT/E11 Activation Loop) CTNIFSPKGIRKSIC SEQ ID NO: 100 (BoNT/E7, E8 and E10 Activation Loop) CKNIVFSKGITKSIC SEQ ID NO: 101 (BoNT/E6 Activation Loop) CKNIVFSKGIRKSIC SEQ ID NO: 102 (BoNT/F7 Activation Loop) CKSIVSKKGTKNSLC SEQ ID NO: 103 (BoNT/F5 Activation Loop) CLNSSFKKNTKKPLC SEQ ID NO: 104 (BoNT/F1 and F6 Activation Loop) CKSVIPRKGTKAPPRLC SEQ ID NO: 105 (BoNT/F4 Activation Loop) CKSIIPRKGTKAPPRLC SEQ ID NO: 106 (BoNT/F2 and F3 Activation Loop) CKSIIPRKGTKQSPSLC SEQ ID NO: 107 (TeNT Activation Loop) CKKIIPPTNIRENLYNRTASLTDLGGELC SEQ ID NO: 108 (BoNT/G Activation Loop) CKPVMYKNTGKSEQC SEQ ID NO: 109 (BoNT/B4 Activation Loop) CKSVKVPGIC SEQ ID NO: 110 (BoNT/B2, B3, B6 and B8 Activation Loop) CKSVRAPGIC SEQ ID NO: 111 (BoNT/B1, B5 and B7 Activation Loop) CKSVKAPGIC SEQ ID NO: 112 (BoNT/X Activation Loop) CPRNGLLYNAIYRNSKNYLNNIDLEDKKTTSKTNVSYPCSLLNGC SEQ ID NO: 113 metal coordinating SNARE cleavage motif HEXXH SEQ ID NO: 114 (TEV cleavage site) ENLYFQG SEQ ID NO: 115 (Thrombin cleavage site) LVPRGS SEQ ID NO: 116 (PreScission cleavage site) LEVLFQGP SEQ ID NO: 117 (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: 118: 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: 119: LC/A1-Cloop-HN/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: 120: LC/X-Cloop-H _N /X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICHKAIDGRSLYNK TLDCIEVENKDLFLI SNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSISQQNILERNEE LYEPIRNSLFEIKTI YVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKNMSNTINSIETG ITSTYIFYQWLRSIV KDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAGITALLEYVPEF TIPILVGLEVIGGEL AREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKALSRQANAIKMN MEFQLANYKGNIDDK AKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETKKTL DKFIKEKEDILGTNL SSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNEGAPAPAPAPAPAS LC/X is italicised BoNT/C activation loop is bold and underlined H _N /X is C-terminal to the C activation loop and is neither underlined nor italicised 2x AP linker are dash-underlined SEQ ID NO: 121: LC/X-EndoSite-H _N /X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKI[EXEMPLARY ENDOSITE] IEVENKDLFLISNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNYDFTEANSIPSI SQQNILERNEELYEP IRNSLFEIKTIYVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALSNPNKVYSPFKN MSNTINSIETGITST YIFYQWLRSIVKDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRHGDFVGAIELAG ITALLEYVPEFTIPI LVGLEVIGGELAREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQINTRLAHTYKA LSRQANAIKMNMEFQ LANYKGNIDDKAKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLTKEMIPKVQDNL KNFDLETKKTLDKFI KEKEDILGTNLSSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNEGAPAPAPAPAP AS LC/X is italicised EndoSite activation loop is bold and underlined H _N /X is C-terminal to the C activation loop and is neither underlined nor italicised 2x AP linker are dash-underlined SEQ ID NO: 122 (additional protease cleavage site) xDxxxLL x is any amino acid SEQ ID NO: 123 (additional protease cleavage site) xExxxLL x is any amino acid SEQ ID NO: 124 (additional protease cleavage site) xExxxIL x is any amino acid SEQ ID NO: 125 (additional protease cleavage site) xExxxLM x is any amino acid SEQ ID NO: 126 (Influenza virus haemagglutinin translocation domain) GLFGAIAGFIENGWEGMIDGWYG SEQ ID NO: 127 (exemplary Endosite exogenous activation loop) CQEAANERQQAKKDFFSSHPLREPVNATEDPDLKNVKSGLTNIKTELVTPARDLFGFVGL F RGHHPDC The AEP cleavage sites (QEAANERQQ, PDLKNVKS and SGLTNIKTE) are shown in bold The CathB cleavage sites (DLFGFVGL and GFVGLFRG) are double-underlined The CathL cleavage sites (QAKKDFFSSHPLREPVNATED, ELVTPARD, RDFGHFGL and GLFRGHHP) are dotted-underlined SEQ ID NO: 128 (exemplary Endosite exogenous activation loop) CQLGKNEEGLFGFVGLFRGHHPDELVTPARDFGHFGLSGLTNIKTEC The AEP cleavage sites (QLGKNEEG and SGLTNIKTE) are shown in bold The CathB cleavage sites (GLFGFVGL and GFVGLFRG) are double-underlined The CathL cleavage sites (GLFRGHHP, ELVTPARD and RDFGHFGL) are dotted- underlined SEQ ID NO: 129 (exemplary Endosite exogenous activation loop) CPGGGNKKIELVTPARDLFGFVGLFRGHHPDLKNVKSKC The AEP cleavage sites (PGGGNKKIE and PDLKNVKSK) are shown in bold The CathB cleavage sites (DLFGFVGL and GFVGLFRG) are double-underlined The CathL cleavage sites (GLFRGHHP and ELVTPARD) are dotted-underlined SEQ ID NO: 130 (exemplary endosomal protease (AEP) cleavage site) PDLKNVKS SEQ ID NO: 131 (exemplary endosomal protease (CathB) cleavage site) DLFGFVGL SEQ ID NO: 132 (exemplary endosomal protease (CathB) cleavage site) GFVGLFRG SEQ ID NO: 133 (exemplary endosomal protease (CathB) cleavage site) GSGLFGFVGGSG SEQ ID NO: 134 (exemplary endosomal protease (CathB) cleavage site) LFGFVGLFGFVG SEQ ID NO: 135 (exemplary endosomal protease (CathB) cleavage site) LFGFVGLFGFVGLFGFVG SEQ ID NO: 136 (exemplary endosomal protease (CathB) cleavage site) GLFGFVGL SEQ ID NO: 137 (exemplary endosomal protease (CathL) cleavage site) QAKKDFFSSHPLREPVNATED SEQ ID NO: 138 (exemplary endosomal protease (CathL) cleavage site) ELVTPARD SEQ ID NO: 139 (exemplary endosomal protease (CathL) cleavage site) RDFGHFGL SEQ ID NO: 140 (exemplary endosomal protease (CathL) cleavage site) GLFRGHHP SEQ ID NO: 141 (exemplary endosomal protease (CathL) cleavage site) GSGLFRGHHPDGSG SEQ ID NO: 142 (exemplary endosomal protease (CathL) cleavage site) LFRGHHPDLFRGHHPD SEQ ID NO: 143 (exemplary endosomal protease (CathL) cleavage site) ELVTPARDFGHFGLS SEQ ID NO: 144 (exemplary endosomal protease (CathL) cleavage site) QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFLGTNE SEQ ID NO: 145 (exemplary endosomal protease (CathL) cleavage site) LFRGHHPDSTSQKSIVAYTMSLGADSS SEQ ID NO: 146 (exemplary endosomal protease (CathL) cleavage site) STSQKSIVAYTMSLGADSSLFRGHHPD SEQ ID NO: 147 (exemplary endosomal protease (CathL) cleavage site) STSQKSIVAYTMSLGADSSSTSQKSIVAYTMSLGADSS SEQ ID NO: 148 (exemplary endosomal protease (CathL) cleavage site) LFRGHHPDLFRGHHPDLFRGHHPD SEQ ID NO: 149 (exemplary endosomal protease (CathL) cleavage site) ELVTPARDFGHFGLSELVTPARDFGHFGLS SEQ ID NO: 150 (exemplary endosomal protease (CathL) cleavage site) STSQKSIVAYTMSLGADSSELVTPARDFGHFGLSLFRGHHPD SEQ ID NO: 151 (exemplary endosomal protease (AEP) cleavage site) QLGKNEEG SEQ ID NO: 152 (exemplary endosomal protease (CathD) cleavage site) GERGFFYTPKT SEQ ID NO: 153 GS spacer consensus sequence (Gly-Gly-Gly-Gly-Ser)n SEQ ID NO: 154 GS5 spacer GGGGS SEQ ID NO: 155 GS10 spacer GGGGSGGGGS SEQ ID NO: 156 GS15 spacer GGGGSGGGGSGGGGS SEQ ID NO: 157 GS20 spacer GGGGSGGGGSGGGGSGGGGS SEQ ID NO: 158 GS25 spacer GGGGSGGGGSGGGGSGGGGSGGGGS SEQ ID NO: 159 exemplary engineered form of the LH _N /A1-H _C B1 chimera MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLN PPPEAKQVPVSYYDS TYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCI NVIQPDGSYRSEELN LVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGA GKFATDPAVTLAHEL IHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLY YYNKFKDIASTLNKA KSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKV LNRKTYLNFDKAVFK INIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGII TSKTKSLDKGYNKAL NDLCQAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFLGTNECIKVNNWDLFFSP SEDNFTNDLNKGEEI TSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGK KYELDKYTMFHYLRA QEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTD ETSEVSTTDKIADIT IIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLT VQTIDNALSKRNEKW DEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNI DDLSSKLNESINKAM ININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKV NNTLSTDIPFQLSKY VDNQRLLSTFTEYIKNILNNIILNLRYKDNNLIDLSGYGAKVEVYDGVELNDKNQFKLTS SANSKIRVTQNQNII FNSVFLDFSVSFWIRIPKYKNDGIQNYIHNEYTIINCMKNNSGWKISIRGNRIIWTLIDI NGKTKSVFFEYNIRE DISEYINRWFFVTITNNLNNAKIYINGKLESNTDIKDIREVIANGEIIFKLDGDIDRTQF IWMKYFSIFNTELSQ SNIEERYKIQSYSEYLKDFWGNPLMYNKEYYMFNAGNKNSYIKLKKDSPVGEILTRSKYN QNSKYINYRDLYIGE KFIIRRKSNSQSINDDIVRKEDYIYLDFFNLNQEWRVYTYKYFKKEEMKLFLAPIYDSDE FYNTIQIKEYDEQPT YSCQLLFKKDEESTDEIGLIGIHRFYESGIVFEEYKDYFCISKWYLKEVKRKPYNLKLGC NWQFIPKDEGWTE LC/A is italicised EndoSite activation loop is bold and underlined HN/A is C-terminal to the EndoSite activation loop and is neither underlined nor italicised SEQ ID NO: 160: Exemplary LC/X-EndoSite-H _N /X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICQEAANERQQAKK DFFSSHPLREPVNAT EDPDLKNVKSGLTNIKTELVTPARDLFGFVGLFRGHHPDCIEVENKDLFLISNKDSLNDI NLSEEKIKPETTVFF KDKLPPQDITLSNYDFTEANSIPSISQQNILERNEELYEPIRNSLFEIKTIYVDKLTTFH FLEAQNIDESIDSSK IRVELTDSVDEALSNPNKVYSPFKNMSNTINSIETGITSTYIFYQWLRSIVKDFSDETGK IDVIDKSSDTLAIVP YIGPLLNIGNDIRHGDFVGAIELAGITALLEYVPEFTIPILVGLEVIGGELAREQVEAIV NNALDKRDQKWAEVY NITKAQWWGTIHLQINTRLAHTYKALSRQANAIKMNMEFQLANYKGNIDDKAKIKNAISE TEILLNKSVEQAMKN TEKFMIKLSNSYLTKEMIPKVQDNLKNFDLETKKTLDKFIKEKEDILGTNLSSSLRRKVS IRLNKNIAFDINDIP FSEFDDLINQYKNEGAPAPAPAPAPAS LC/X is italicised EndoSite activation loop is bold and underlined H _N /X is C-terminal to the C activation loop and is neither underlined nor italicised 2x AP linker are dash-underlined SEQ ID NO: 161: Exemplary LC/X-EndoSite-H _N /X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICPGGGNKKIELVT PARDLFGFVGLFRGH HPDLKNVKSKCIEVENKDLFLISNKDSLNDINLSEEKIKPETTVFFKDKLPPQDITLSNY DFTEANSIPSISQQN ILERNEELYEPIRNSLFEIKTIYVDKLTTFHFLEAQNIDESIDSSKIRVELTDSVDEALS NPNKVYSPFKNMSNT INSIETGITSTYIFYQWLRSIVKDFSDETGKIDVIDKSSDTLAIVPYIGPLLNIGNDIRH GDFVGAIELAGITAL LEYVPEFTIPILVGLEVIGGELAREQVEAIVNNALDKRDQKWAEVYNITKAQWWGTIHLQ INTRLAHTYKALSRQ ANAIKMNMEFQLANYKGNIDDKAKIKNAISETEILLNKSVEQAMKNTEKFMIKLSNSYLT KEMIPKVQDNLKNFD LETKKTLDKFIKEKEDILGTNLSSSLRRKVSIRLNKNIAFDINDIPFSEFDDLINQYKNE GAPAPAPAPAPAS LC/X is italicised EndoSite activation loop is bold and underlined H _N /X is C-terminal to the C activation loop and is neither underlined nor italicised 2x AP linker are dash-underlined SEQ ID NO: 162: Exemplary LC/X-EndoSite-H _N /X MKLEINKFNYNDPIDGINVITMRPPRHSDKINKGKGPFKAFQVIKNIWIVPERYNFTNNT NDLNIPSEPIMEADA IYNPNYLNTPSEKDEFLQGVIKVLERIKSKPEGEKLLELISSSIPLPLVSNGALTLSDNE TIAYQENNNIVSNLQ ANLVIYGPGPDIANNATYGLYSTPISNGEGTLSEVSFSPFYLKPFDESYGNYRSLVNIVN KFVKREFAPDPASTL MHELVHVTHNLYGISNRNFYYNFDTGKIETSRQQNSLIFEELLTFGGIDSKAISSLIIKK IIETAKNNYTTLISE RLNTVTVENDLLKYIKNKIPVQGRLGNFKLDTAEFEKKLNTILFVLNESNLAQRFSILVR KHYLKERPIDPIYVN ILDDNSYSTLEGFNISSQGSNDFQGQLLESSYFEKIESNALRAFIKICQLGKNEEGLFGF VGLFRGHHPDELVTP ARDFGHFGLSGLTNIKTECIEVENKDLFLISNKDSLNDINLSEEKIKPETTVFFKDKLPP QDITLSNYDFTEANS IPSISQQNILERNEELYEPIRNSLFEIKTIYVDKLTTFHFLEAQNIDESIDSSKIRVELT DSVDEALSNPNKVYS PFKNMSNTINSIETGITSTYIFYQWLRSIVKDFSDETGKIDVIDKSSDTLAIVPYIGPLL NIGNDIRHGDFVGAI ELAGITALLEYVPEFTIPILVGLEVIGGELAREQVEAIVNNALDKRDQKWAEVYNITKAQ WWGTIHLQINTRLAH TYKALSRQANAIKMNMEFQLANYKGNIDDKAKIKNAISETEILLNKSVEQAMKNTEKFMI KLSNSYLTKEMIPKV QDNLKNFDLETKKTLDKFIKEKEDILGTNLSSSLRRKVSIRLNKNIAFDINDIPFSEFDD LINQYKNEGAPAPAP APAPAS LC/X is italicised EndoSite activation loop is bold and underlined H _N /X is C-terminal to the C activation loop and is neither underlined nor italicised 2x AP linker are dash-underlined SEQ ID NO: 163: Exemplary nucleic acid encoding LC/X-Cloop-H _N /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 agcgaattcgatgatctgatcaaccagtacaaaaatgaaggtgcaccggcaccagctcca gcgccagcaccggca agt nucleic acid encoding the Cloop is bold and underlined nucleic acid encoding 2xAP linker is dash underlined SEQ ID NO: 164: Exemplary nucleic acid Cloop tgtcataaagccattgatggtcgcagcctgtataacaaaaccctggat SEQ ID NO: 165: Exemplary nucleic acid encoding the exogenous activation loop of SEQ ID NO: 127 TGTCAGGAAGCCGCTAACGAGAGACAGCAGGCCAAGAAAGACTTTTTTAGTAGTCATCCT CTGAGAGAACCCGTG AATGCGACTGAAGATCCCGATCTGAAGAACGTTAAAAGCGGGCTCACAAATATCAAAACC GAGCTCGTTACCCCG GCTCGTGACCTGTTTGGCTTCGTAGGATTATTCCGTGGACACCATCCAGACTGC SEQ ID NO: 166: Exemplary nucleic acid encoding the exogenous activation loop of SEQ ID NO: 128 TGCCAGTTAGGTAAAAACGAAGAAGGCTTGTTTGGCTTCGTCGGTCTTTTTAGAGGCCAC CATCCGGACGAACTT GTTACTCCTGCGCGCGATTTTGGGCATTTCGGTCTGTCTGGACTCACCAATATTAAAACC GAATGT SEQ ID NO: 167: Exemplary nucleic acid encoding the exogenous activation loop of SEQ ID NO: 129 TGTCCTGGTGGGGGTAACAAGAAAATTGAGCTCGTCACCCCCGCGCGTGATCTGTTTGGA TTTGTTGGGCTGTTC CGTGGCCACCATCCTGACTTAAAAAACGTTAAAAGCAAATGT SEQ ID NO: 168: Exemplary nucleic acid encoding engineered re-targeted BoNT/X comprising the exogenous activation loop of SEQ ID NO: 127 atgaaattagaaataaataaatttaattataatgatccaatagatggtattaatgtaatt actatgagaccacct aggcattcagataaaattaataaaggaaaaggaccatttaaagcttttcaagttataaaa aatatatggatagta cctgaaagatataatttcacaaataataccaatgatttaaatataccatctgaaccaatt atggaggctgatgct atttataatcctaattatttaaatactccatccgaaaaagatgagtttttacaaggcgta attaaagttttagaa agaataaaaagtaaacctgaaggagagaagctattagaattaattagctcttcaattccg cttcctttagtttct aatggtgcattaactttatcagataatgaaactattgcttatcaagaaaataataatata gtatctaatcttcaa gctaatttagttatttatggtcctggtccagacatagcaaataatgctacttatggattg tacagtactccaatt tcaaatggagaaggaacactgagtgaagtttcgttttcaccattttatttaaaacctttt gatgaatcttatgga aattatagatcacttgtgaatatagtgaataagtttgtaaagagagaatttgctccggat ccagcatcaactttg atgcacgagctagtacatgttacccacaatttatatggtattagcaatagaaatttttat tataattttgatact ggtaaaatagaaacctcaagacaacaaaatagtttaatttttgaagaactcttaacattt ggaggaattgattca aaagctataagttcgttaatcattaaaaagataatagagacggctaaaaataactataca acattaatatcagaa agacttaatactgtaacggttgaaaatgacttattaaaatatataaagaataagattccg gtacaaggtagattg ggtaactttaaacttgatactgcagagtttgaaaagaaactgaatactatactatttgta ttaaatgaatcaaat ttggctcagagattttcaatattagttagaaaacattacttaaaagaaagacctatagat cctatttatgttaat attttggatgacaattcctactctactttagaaggatttaatattagttcacaaggtagt aatgattttcaagga cagcttcttgaatcatcttattttgaaaaaatagaaagtaatgctttaagggctttcata aaaataTGTCAGGAA GCCGCTAACGAGAGACAGCAGGCCAAGAAAGACTTTTTTAGTAGTCATCCTCTGAGAGAA CCCGTGAATGCGACT GAAGATCCCGATCTGAAGAACGTTAAAAGCGGGCTCACAAATATCAAAACCGAGCTCGTT ACCCCGGCTCGTGAC CTGTTTGGCTTCGTAGGATTATTCCGTGGACACCATCCAGACTGCattgaagtagaaaat aaagatttattctta attagtaataaagattcattaaatgatataaatttaagtgaagaaaaaattaagccagaa acaacagtgtttttc aaagacaaattaccaccacaagatataacattaagtaattatgattttacagaagctaac tctataccttcaata tctcaacaaaacattttagaaagaaatgaagaactttatgaaccaattagaaatagttta tttgaaataaaaacc atatatgttgataagttaactacttttcattttcttgaagctcaaaatatagatgaaagt attgattcttcaaaa ataagagtcgaattaacagattctgtagatgaggcgttatcaaacccaaataaggtttat tctccatttaaaaat atgtctaacactattaattctattgaaacagggattacatctacgtatatattttaccaa tggttaagaagtatt gtaaaagattttagtgacgaaacaggtaaaatagatgtaatagataaatcaagtgatact cttgctatagtacct tatataggacctctactaaatataggtaatgatattcgtcatggtgattttgttggagct atagagcttgcagga attactgctttgcttgaatatgttcctgaattcacaatacctatattggtaggattagaa gttattggcggtgaa cttgctagagaacaagtagaagcaattgtaaataatgcattagataaacgtgatcaaaaa tgggctgaagtttat aatattacaaaagctcaatggtggggaacaattcatttacaaataaatactagactagct catacttataaggcg ctatcaagacaagcaaatgctatcaaaatgaatatggaatttcaacttgccaattataaa ggaaatattgatgat aaggctaagataaaaaatgcaatcagtgaaactgaaattttattaaataaatcagtagaa caggctatgaaaaat actgaaaaatttatgataaagttatcaaactcatatttaacaaaggaaatgattccaaaa gtacaagataatctg aaaaattttgatttagaaactaaaaagactttagataaattcataaaagaaaaagaagat atacttggtacaaat ttatctagcagtttaagaaggaaagtctcaatacgacttaataaaaatatagctttcgat attaatgatattcca ttctctgaatttgacgatttaataaatcaatataaaaatgaaggtgcacccgcacctgca ccagctccagctccg gcgagc nucleic acid encoding the Cloop is bold and underlined nucleic acid encoding 2xAP linker is dash underlined SEQ ID NO: 169: Exemplary nucleic acid encoding engineered re-targeted BoNT/X comprising the exogenous activation loop of SEQ ID NO: 128 atgaaattagaaataaataaatttaattataatgatccaatagatggtattaatgtaatt actatgagaccacct aggcattcagataaaattaataaaggaaaaggaccatttaaagcttttcaagttataaaa aatatatggatagta cctgaaagatataatttcacaaataataccaatgatttaaatataccatctgaaccaatt atggaggctgatgct atttataatcctaattatttaaatactccatccgaaaaagatgagtttttacaaggcgta attaaagttttagaa agaataaaaagtaaacctgaaggagagaagctattagaattaattagctcttcaattccg cttcctttagtttct aatggtgcattaactttatcagataatgaaactattgcttatcaagaaaataataatata gtatctaatcttcaa gctaatttagttatttatggtcctggtccagacatagcaaataatgctacttatggattg tacagtactccaatt tcaaatggagaaggaacactgagtgaagtttcgttttcaccattttatttaaaacctttt gatgaatcttatgga aattatagatcacttgtgaatatagtgaataagtttgtaaagagagaatttgctccggat ccagcatcaactttg atgcacgagctagtacatgttacccacaatttatatggtattagcaatagaaatttttat tataattttgatact ggtaaaatagaaacctcaagacaacaaaatagtttaatttttgaagaactcttaacattt ggaggaattgattca aaagctataagttcgttaatcattaaaaagataatagagacggctaaaaataactataca acattaatatcagaa agacttaatactgtaacggttgaaaatgacttattaaaatatataaagaataagattccg gtacaaggtagattg ggtaactttaaacttgatactgcagagtttgaaaagaaactgaatactatactatttgta ttaaatgaatcaaat ttggctcagagattttcaatattagttagaaaacattacttaaaagaaagacctatagat cctatttatgttaat attttggatgacaattcctactctactttagaaggatttaatattagttcacaaggtagt aatgattttcaagga cagcttcttgaatcatcttattttgaaaaaatagaaagtaatgctttaagggctttcata aaaataTGCCAGTTA GGTAAAAACGAAGAAGGCTTGTTTGGCTTCGTCGGTCTTTTTAGAGGCCACCATCCGGAC GAACTTGTTACTCCT GCGCGCGATTTTGGGCATTTCGGTCTGTCTGGACTCACCAATATTAAAACCGAATGTatt gaagtagaaaataaa gatttattcttaattagtaataaagattcattaaatgatataaatttaagtgaagaaaaa attaagccagaaaca acagtgtttttcaaagacaaattaccaccacaagatataacattaagtaattatgatttt acagaagctaactct ataccttcaatatctcaacaaaacattttagaaagaaatgaagaactttatgaaccaatt agaaatagtttattt gaaataaaaaccatatatgttgataagttaactacttttcattttcttgaagctcaaaat atagatgaaagtatt gattcttcaaaaataagagtcgaattaacagattctgtagatgaggcgttatcaaaccca aataaggtttattct ccatttaaaaatatgtctaacactattaattctattgaaacagggattacatctacgtat atattttaccaatgg ttaagaagtattgtaaaagattttagtgacgaaacaggtaaaatagatgtaatagataaa tcaagtgatactctt gctatagtaccttatataggacctctactaaatataggtaatgatattcgtcatggtgat tttgttggagctata gagcttgcaggaattactgctttgcttgaatatgttcctgaattcacaatacctatattg gtaggattagaagtt attggcggtgaacttgctagagaacaagtagaagcaattgtaaataatgcattagataaa cgtgatcaaaaatgg gctgaagtttataatattacaaaagctcaatggtggggaacaattcatttacaaataaat actagactagctcat acttataaggcgctatcaagacaagcaaatgctatcaaaatgaatatggaatttcaactt gccaattataaagga aatattgatgataaggctaagataaaaaatgcaatcagtgaaactgaaattttattaaat aaatcagtagaacag gctatgaaaaatactgaaaaatttatgataaagttatcaaactcatatttaacaaaggaa atgattccaaaagta caagataatctgaaaaattttgatttagaaactaaaaagactttagataaattcataaaa gaaaaagaagatata cttggtacaaatttatctagcagtttaagaaggaaagtctcaatacgacttaataaaaat atagctttcgatatt aatgatattccattctctgaatttgacgatttaataaatcaatataaaaatgaaggtgca cccgcacctgcacca gctccagctccggcgagc nucleic acid encoding the Cloop is bold and underlined nucleic acid encoding 2xAP linker is dash underlined SEQ ID NO: 170: Exemplary nucleic acid encoding engineered re-targeted BoNT/X comprising the exogenous activation loop of SEQ ID NO: 129 atgaaattagaaataaataaatttaattataatgatccaatagatggtattaatgtaatt actatgagaccacct aggcattcagataaaattaataaaggaaaaggaccatttaaagcttttcaagttataaaa aatatatggatagta cctgaaagatataatttcacaaataataccaatgatttaaatataccatctgaaccaatt atggaggctgatgct atttataatcctaattatttaaatactccatccgaaaaagatgagtttttacaaggcgta attaaagttttagaa agaataaaaagtaaacctgaaggagagaagctattagaattaattagctcttcaattccg cttcctttagtttct aatggtgcattaactttatcagataatgaaactattgcttatcaagaaaataataatata gtatctaatcttcaa gctaatttagttatttatggtcctggtccagacatagcaaataatgctacttatggattg tacagtactccaatt tcaaatggagaaggaacactgagtgaagtttcgttttcaccattttatttaaaacctttt gatgaatcttatgga aattatagatcacttgtgaatatagtgaataagtttgtaaagagagaatttgctccggat ccagcatcaactttg atgcacgagctagtacatgttacccacaatttatatggtattagcaatagaaatttttat tataattttgatact ggtaaaatagaaacctcaagacaacaaaatagtttaatttttgaagaactcttaacattt ggaggaattgattca aaagctataagttcgttaatcattaaaaagataatagagacggctaaaaataactataca acattaatatcagaa agacttaatactgtaacggttgaaaatgacttattaaaatatataaagaataagattccg gtacaaggtagattg ggtaactttaaacttgatactgcagagtttgaaaagaaactgaatactatactatttgta ttaaatgaatcaaat ttggctcagagattttcaatattagttagaaaacattacttaaaagaaagacctatagat cctatttatgttaat attttggatgacaattcctactctactttagaaggatttaatattagttcacaaggtagt aatgattttcaagga cagcttcttgaatcatcttattttgaaaaaatagaaagtaatgctttaagggctttcata aaaataTGTCCTGGT GGGGGTAACAAGAAAATTGAGCTCGTCACCCCCGCGCGTGATCTGTTTGGATTTGTTGGG CTGTTCCGTGGCCAC CATCCTGACTTAAAAAACGTTAAAAGCAAATGTattgaagtagaaaataaagatttattc ttaattagtaataaa gattcattaaatgatataaatttaagtgaagaaaaaattaagccagaaacaacagtgttt ttcaaagacaaatta ccaccacaagatataacattaagtaattatgattttacagaagctaactctataccttca atatctcaacaaaac attttagaaagaaatgaagaactttatgaaccaattagaaatagtttatttgaaataaaa accatatatgttgat aagttaactacttttcattttcttgaagctcaaaatatagatgaaagtattgattcttca aaaataagagtcgaa ttaacagattctgtagatgaggcgttatcaaacccaaataaggtttattctccatttaaa aatatgtctaacact attaattctattgaaacagggattacatctacgtatatattttaccaatggttaagaagt attgtaaaagatttt agtgacgaaacaggtaaaatagatgtaatagataaatcaagtgatactcttgctatagta ccttatataggacct ctactaaatataggtaatgatattcgtcatggtgattttgttggagctatagagcttgca ggaattactgctttg cttgaatatgttcctgaattcacaatacctatattggtaggattagaagttattggcggt gaacttgctagagaa caagtagaagcaattgtaaataatgcattagataaacgtgatcaaaaatgggctgaagtt tataatattacaaaa gctcaatggtggggaacaattcatttacaaataaatactagactagctcatacttataag gcgctatcaagacaa gcaaatgctatcaaaatgaatatggaatttcaacttgccaattataaaggaaatattgat gataaggctaagata aaaaatgcaatcagtgaaactgaaattttattaaataaatcagtagaacaggctatgaaa aatactgaaaaattt atgataaagttatcaaactcatatttaacaaaggaaatgattccaaaagtacaagataat ctgaaaaattttgat ttagaaactaaaaagactttagataaattcataaaagaaaaagaagatatacttggtaca aatttatctagcagt ttaagaaggaaagtctcaatacgacttaataaaaatatagctttcgatattaatgatatt ccattctctgaattt gacgatttaataaatcaatataaaaatgaaggtgcacccgcacctgcaccagctccagct ccggcgagc nucleic acid encoding the Cloop is bold and underlined nucleic acid encoding 2xAP linker is dash underlined SEQ ID NO: 171: Exemplary Cathepsin L cleavage site GYYSTTIRYQATGFGTNE SEQ ID NO: 172: Exemplary Cathepsin L cleavage site LFRGHHPD SEQ ID NO: 173: Exemplary Cathepsin L cleavage site GLFRGHHPD SEQ ID NO: 174: Exemplary Cathepsin L cleavage site QAKKDFFSSHPLREPVNATEDPSSGYYSTTIRYQATGFGTNEP SEQ ID NO: 175: Exemplary Cathepsin L cleavage site QAKKDFFSSHPL SEQ ID NO: 176: Exemplary Cathepsin L cleavage site REPVNATEDPSSGYYS SEQ ID NO: 177: Exemplary Cathepsin L cleavage site TTIRYQATGFGTNE SEQ ID NO: 178: Exemplary Cathepsin L cleavage site TTIRYQATGFGTNEP SEQ ID NO: 179: Exemplary Cathepsin L cleavage site EVDLLIGSS SEQ ID NO: 180: Exemplary Cathepsin L cleavage site EVDLLIGSSGE SEQ ID NO: 181: Exemplary Cathepsin B cleavage site GLAGFLGG SEQ ID NO: 182: Exemplary Cathepsin B cleavage site GLFGFVGG SEQ ID NO: 183: Exemplary Cathepsin B cleavage site TVGSFGFE SEQ ID NO: 184: Exemplary Cathepsin B cleavage site TVGSFGFEGG SEQ ID NO: 185: Exemplary Cathepsin D cleavage site LASLLELPEFLLFLQ SEQ ID NO: 186: Exemplary Cathepsin D cleavage site GLTTELFSPVD SEQ ID NO: 187: Exemplary AEP cleavage site LERNSNLVGAA SEQ ID NO: 188:core Cathepsin L cleavage motif MSLGADSS SEQ ID NO: 189:core Cathepsin L cleavage motif LFRGHHP SEQ ID NO: 190:core Cathepsin L cleavage motif GLFRGHHP SEQ ID NO: 191:core Cathepsin L cleavage motif KDFFSSHP SEQ ID NO: 192:core Cathepsin L cleavage motif EPVNATED SEQ ID NO: 193:core Cathepsin L cleavage motif TGFGTNE SEQ ID NO: 194:core Cathepsin L cleavage motif TGFGTNEP SEQ ID NO: 195:core Cathepsin L cleavage motif QKVGKAMY SEQ ID NO: 196:core Cathepsin L cleavage motif LLIGSS SEQ ID NO: 197:core Cathepsin L cleavage motif LLIGSSGE SEQ ID NO: 198:core Cathepsin B cleavage motif GSFGFE SEQ ID NO: 199:core Cathepsin B cleavage motif GSFGFEGG SEQ ID NO: 200:core Cathepsin D cleavage motif VEKLLELK SEQ ID NO: 201:core Cathepsin D cleavage motif VITLVMLK SEQ ID NO: 202:core Cathepsin D cleavage motif GMELIVSQ SEQ ID NO: 203:core Cathepsin D cleavage motif QPYLEMDL SEQ ID NO: 204:core Cathepsin D cleavage motif EYALLYKL SEQ ID NO: 205:core Cathepsin D cleavage motif LAEEEVVI SEQ ID NO: 206:core Cathepsin D cleavage motif LASLLELP SEQ ID NO: 207:core Cathepsin D cleavage motif TTELFSPV SEQ ID NO: 208:core AEP cleavage motif EAANERQQ SEQ ID NO: 209:core AEP cleavage motif GLTNIKTE SEQ ID NO: 210:core AEP cleavage motif DLKNVKSK SEQ ID NO: 211:core AEP cleavage motif GGGNKKIE SEQ ID NO: 212:core AEP cleavage motif LGKNEEGA SEQ ID NO: 213:core AEP cleavage motif ERNSNLV SEQ ID NO: 214:core AEP cleavage motif LERNSNLV 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 endosomal 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 BoNT engineered to comprise endosomal 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, His tag (optionally cleavable) and 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 three engineered BoNT with the structure LC/A1-Cloop-H _N /A1-EndoSite-TM-His ₆ : EndoSite = CatDReo (BIO4934), Ebo (BIO4935), and CatBL (BIO4945)). 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 endosomal protease cleavage sites and combinations thereof. The pre-engineering LC/A1-Cloop-H _N /A1 sequence for each of these engineered BoNT is SEQ ID NO: 119. BIO4934 comprises the endosomal protease cleavage site of SEQ ID NO: 35, which itself comprises a cleavage site for cathepsin D and two cleavage sites for cathepsin L. BIO4935 comprises the endosomal protease cleavage site of SEQ ID NO: 36, which itself comprises two cleavage sites for cathepsin L. BIO4945 comprises the endosomal protease cleavage site of SEQ ID NO: 37, which itself comprises a cleavage site for cathepsin B and two cleavage sites for cathepsin L. By way of a pH control, samples of each of CatDReo (BIO4934), Ebo (BIO4935), and CatBL (BIO4945) were incubated in 1mM DTT with either PBS at pH 7.2 or 50mM MES at pH 5, at room temperature for 3 hours without the corresponding endosomal protease, and then reduced for analysis. As shown in Figure 1A, when run on a Coomassie gel, a fainter band corresponding to the full-length engineered BoNT was visible at pH 7.2 compared with pH 5 for all of CatDReo (BIO4934), Ebo (BIO4935), and CatBL (BIO4945). The LC/A1 band and HN/A1-EndoSite-TM- His6 bands were similar in strength at both pHs. A faint band at >20 kDa was observed for all of CatDReo (BIO4934), Ebo (BIO4935), and CatBL (BIO4945), indicative of an impurity. Significantly, no band was visible (at pH 7.2 or pH 5) at ~15 kDa demonstrating that cleavage at the EndoSite in the absence of the corresponding endosomal protease was zero/below the limits of detection/negligible by protein detection. Western blots using anti-LC/A1 (Figure 1B) and anti-His tag (data not shown) antibodies were also performed. As shown in Figure 1B, using the anti-LC/A1 antibody, there was no difference in signal intensity for the full-length bands or the LC/A1 band and H _N /A1- EndoSite-TM-His ₆ bands at the two pHs. Faint bands were observed at ~30 kDa and ~ 20kDa, and also at >50 kDa. This suggests the present of impurities and/or cross-reactivity with the H _N /A1-EndoSite-TM-His ₆ chain, likely as an artefact of the over-exposure of the Western blots. Notwithstanding this, no band was visible (at pH 7.2 or pH 5) at ~15 kDa demonstrating that cleavage at the EndoSite in the absence of the corresponding endosomal protease was zero/below the limits of detection/negligible. Using the anti-His tag antibody, it was again confirmed that the buffer pH did not have a significant impact on CatDReo (BIO4934), Ebo (BIO4935), and CatBL (BIO4945). Some faint bands were observed at <20kDa. It is hypothesised that these may be artefactual cross- reactivities or impurities, or trace amounts of truncated products that can only be detected by overexposed Western blots. Example 2 – BoNT engineered to comprise an Cathepsin L1 cleavage site are effectively cleaved by Cathepsin L1 Three engineered BoNT produced in Example 1 (LC/A1-Cloop-H _N /A1-EndoSite-TM- His ₆ , where EndoSite = CatDReo (BIO4934), Ebo (BIO4935), or CatBL (BIO4945)) were investigated. The ability of cathepsin L to cleave BIO4934, BIO4935 and BIO4945 was tested by incubating 90µg/mL mg/mL of each engineered BoNT with a serial dilution of Cathepsin L1 for 2 hours at room temperature in 50 mM MES pH 5, reduced with DTT, and resolved by SDS PAGE for Coomassie staining and Western blot analysis. BIO4934, BIO4935 and BIO4945 are each approx.118 kDa (composed of approx.100 kDa LHN/A + approx.18 kDa TM-HT). All of BIO4934 , BIO4935 and BIO4945 were sensitive to Cathepsin L, with cleavage yielding a doublet of approx.50 kDa (LC/A & HN/A, when reduced) band and a >15 kDa TM-HT band. Cleavage of each of the BIO4934, BIO4935 and BIO4945 engineered BoNTs was concentration-dependent, with even low concentrations of Cathepsin L1 (14 ng/mL) achieving some degree of cleavage). Exemplary data for BIO4934 and BIO4935 is shown in Figure 2A and 2B respectively. Therefore, these data demonstrate that cathepsin L can be used successfully to cleave and hence activate BIO4934, BIO4935 and BIO4945 engineered BoNTs. Example 3 – BoNT engineered to comprise an Cathepsin B cleavage site is effectively cleaved by Cathepsin B The CatBL (BIO4945) engineered BoNT produced in Example 1 was investigated for its sensitivity to Cathepsin B. The ability of cathepsin B to cleave BIO4945 was tested by incubating 0.3 mg/mL of CatBL (BIO4945) with a serial dilution of Cathepsin B for 2 hours at room temperature in 50 mM MES pH 5, reduced with DTT, and resolved by SDS PAGE for Coomassie staining and Western blot analysis. As shown in Figure 3, BIO4945 is sensitive to Cathepsin B, with cleavage yielding a doublet of approx.50 kDa (LC/A & H _N /A, when reduced) band and a >15 kDa TM-HT band. Cleavage of BIO4945 engineered BoNT was concentration-dependent, with even low concentrations of Cathepsin B (5 ng/mL) achieving some degree of cleavage. Therefore, these data demonstrate that cathepsin B can be used successfully to cleave and hence activate BIO4935 engineered BoNT. Example 4 – BoNT engineered to comprise an asparaginyl endopeptidase cleavage sites are effectively cleaved by asparaginyl endopeptidase A further engineered BoNT produced was produced with the same TM, LC/A1, and H _N /A1, as described in Example 1 to 3, but with an AEP cleavage site (LC/A1-Cloop-H _N /A1- EndoSite-TM-His ₆ , where EndoSite = AEP (BIO4938)), was investigated. BIO4938 comprises the endosomal protease cleavage site of SEQ ID NO: 38, which itself comprises five cleavage sites for AEP. 150 µg/mL BIO4938 was incubated with a serial dilution of AEP at room temperature for ~2 hours in 50 mM MES pH 5, and reduced for analysis. BIO4938 is approx.119 kDa (composed of approx.100 kDa LHN/A + approx.19 kDa AEP-TM-HT). As shown in Figure 4, BIO4938 is sensitive to AEP, with cleavage yielding a doublet of approx.50 kDa (LC/A & HN/A, when reduced) band and a >15 kDa TM-HT band. Cleavage of BIO4938 engineered BoNT was concentration-dependent, with even low concentrations of AEP B (7 ng/mL) achieving some degree of cleavage). Example 5 – design and production of retargeted BoNT/X with the endogenous activation loop engineered to comprise endosomal protease cleavage sites The method of Example 1 is repeated to produce an engineered BoNT derived from a retargeted BoNT/X molecule. The engineered BoNT/X is derived from a retargeted BoNT/X with the structure LC/X-Cloop-HN/X-2xAP linker-TM-tag, where the LC/X-Cloop-HN/X-2xAP linker has a sequence as shown in SEQ ID NO: 120 and the tag is a cleavable affinity purification tag, such as a His-tag. Alternatively, the engineered BoNT/X is derived from a retargeted BoNT/X having an N-terminal tag, which has the structure tag-LC/X-Cloop-HN/X- 2xAP linker-TM. The tag is optionally cleavable. The BoNT/C activation loop is replaced with an EndoSite activation loop of choice, such as SEQ ID NO: 127-129. Thus, the engineered retargeted BoNT/X has the structure LC/X-EndoSite-H _N /X-2xAP linker-TM-tag or tag-LC/X- EndoSite-H _N /X-2xAP linker-TM, wherein the LC/X-EndoSite-H _N /X-2xAP linker has a sequence as shown in SEQ ID NO: 160-162. Thus, LC/X-EndoSite-H _N /X-2xAP is sensitive to one or more of AEP, Cathepsin B and/or Cathepsin L. A set concentration of LC/X-Cloop-H _N /X-2xAP linker-TM-tag or tag-LC/X-EndoSite- H _N /X-2xAP linker-TM is treated with serial dilutions of AEP, Cathepsin B or Cathepsin L and incubated for 2 hours at room temperature. Samples are reduced with DTT and analysed by SDS PAGE and Western blot (anti-tag) to assess EndoSite cleavage by AEP, Cathepsin B or Cathepsin L compared to untreated. The protein gel shows a decrease in intensity of the single band of the single chain with an appearance and concomitant increase in intensity of two smaller bands representing the active di-chain. The anti-tag blot shows a similar result, except that the smaller of the two bands is missing as this is the untagged LC. Target cells (e.g., primary cortical neurons) are treated with serial dilutions of LC/X- Cloop-H _N /X-2xAP linker-TM-tag or tag-LC/X-EndoSite-H _N /X-2xAP linker-TM in triplicate wells and incubated for 24 hours. Thereafter, cells are harvested and lysed with 1x NuPAGE buffer, DTT, and Benzonase. The lysates are then analysed by Western blot for substrate cleavage by LC/X (e.g., VAMP2, VAMP4, or Ykt6) by measuring the disappearance of the substrate band and the appearance of a cleaved fragment band by densitometry. The amount of cleaved substrate is expressed as a percentage of the sum of uncleaved and cleaved substrate, and the concentration of target molecule required to cause half maximal cleavage of substrate (EC50) calculated by non-linear regression. This is compared to cleavage activity of the corresponding molecule without an EndoSite (e.g., Cloop, LC/X-Cloop-HN/X-2xAP linker-TM- tag, or native Xloop, LC/X-Xloop-HN/X-2xAP linker-TM-tag or tag-LC/X-Xloop-HN/X-2xAP linker-TM). Single chain LC/X-EndoSite-HN/X-2xAP linker-TM-tag or tag-LC/X-EndoSite-HN/X- 2xAP linker-TM shows cleavage of the substrate whereas the corresponding single chain non- EndoSite retargeted BoNT/X (LC/X-Cloop-HN/X-2xAP linker-TM-tag, tag-LC/X-Cloop-HN/X- 2xAP linker-TM, LC/X-Xloop-HN/X-2xAP linker-TM-tag or tag-LC/X-Xloop-HN/X-2xAP linker- TM) shows no/minimal cleavage. 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.