Topical compositions Field of the Invention

The present invention relates to a topical cosmetic or pharmaceutical compositions. Background to the Invention

Many topical cosmetic and pharmaceutical compositions have been described. Improvement is always desirable.

Currently, there are different approaches for improving muscle health or muscle-glucose- absorption. However, finding an alternative that helps muscle recover and maintenance is desirable. Furthermore, finding an alternative that also allows glucose to enter the muscle without targeting the insulin receptor is becoming essential for the billions of people suffering from, muscle loss and diabetes,

Maintaining a normal level of inflammation is very important for our health and wellbeing, both inside and out. Unfortunately, inflammation is on the rise, One of the major factors of this increase comes from our exposure to an increasing variety of external agents that our bodies are not accustomed to. Most anti-inflammatory treatments used today arc drugs. These drugs however have drastic side-effects. Therefore, there is a clear need for the identification of agents having anti-inflammatory activity that are not immunosuppressive and/or cause other undesirable side effects.

The growing will of maintaining a youthful appearance is leading to more and more research of new dermatological procedures for treatment, of skin aging, especially when people keeps living longer and healthier. Recently, there has been an increasing enthusiasm on minimally invasive treatments and techniques designed to deal with problems like wrinkles, volume loss and other skin damages. The most common topical anti-ageing solutions are creams and serums.

US2004/0132667 discloses compositions comprising tertrapeptides, optionally in combination with one or more additional ingredients. The compositions disclosed provide relief from one or more skin conditions, including those caused by various sources of stress, pollution and general aging. US2014/0120141 discloses cosmetic and pharmaceutical compositions containing peptides for use in the treatment and/or care of conditions, disorders and/or diseases of the skin and/or mucous membranes, It is an object of the invention to overcome at least one of the above-referenced problems and provide a topical composition.

Summary

A first aspect of the invention provides a topical, cosmetic or pharmaceutical, composition (hereinafter "topical composition of the invention") comprising a cosmetically or pharmaceutically effective amount of a peptide comprising an amino acid sequence of SEQUENCE ID NO. 1 or a variant thereof (hereafter "peptide of the invention").

Preferably, said peptide is a bioactive peptide.

Typically, said variant is a bioactive variant. Suitably, the topical composition comprises a plurality of peptides.

Typically, the topical composition further comprises at least one cosmetically or pharmaceutically acceptable excipicnt or additive.

Typically, the topical composition further comprises at least one cosmetically or pharmaceutically acceptable active. Suitably, the peptide comprises an amino acid sequence consisting of SEQUENCE ID NO. 1.

Typically, said variant or bioactive variant has from about 70% to about 99% sequence identity with SEQUENCE ID NO. 1.

Typically, said variant or bioactive variant has at least about 70%, 75%, 80%. 85%, 90% or 95% sequence identity with SEQUENCE ID NO. 1.

Preferably, said variant or bioactive variant has an amino acid sequence comprising any SEQUENCE ID NO. 3 to 80. Preferably, said variant or bioactive variant has an amino acid sequence comprising any one of SEQUENCE ID NO. 3 to 80 and 84 to 114.

Typically, said variant or bioactive variant has an amino acid sequence consisting of any one of SEQUENCE ID NO.3 to 80.

Typically, said variant or bioactive variant has an amino acid sequence consisting of any one of SEQUENCE ID NO. 3 to 80 and 84 to 1 14

Typically, said peptide comprises from about 3 to about 50 amino acids in length. Preferably from about 5 to about 20 amino acids in length, preferably about 14 amino acids in length.

Typically, said variant comprises from about 3 to about 50 amino acids in length. Preferably from about 5 to about 20 amino acids in length, preferably about 14 amino acids in length.

Typically, said variant is a fragment of SEQ ID NO. 1 comprising at least three amino acids in length. Typically, said fragment is bioactive. Typically, said fragment has one or more of antiinflammatory activity, cellular growth promoting activity, anti-aging activity and glucose transport-promoting activit .

Alternatively, said variant is a fragment of SEQ ID NO. 1 having at least 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 amino acids in length.

Suitably, the peptide or variant has anti -inflammatory activity.

Suitably, the peptide or variant has cellular growth promoting activity. Suitably, the peptide or variant has anti-aging activity. Suitably, the peptide or variant has glucose transport-promoting activity. The peptide or variant may have one or more of anti-inflammatory activity, glucose transport- promoting activity, cellular growth promoting activity and anti-aging activity. The peptide or variant may have anti-inflammatory activity, glucose transport-promoting activity, cellular growth promoting activity and anti -aging activity.

Still preferred, the peptide comprises (or consists of) an amino acid sequence of SEQUENCE ID ^" NO'S 1, or the variant comprises (or consists of) an amino acid sequence of SEQUENCE ID NO. 3 to 80 and 84 to 1 14, wherein the peptide or variant typically has glucose transport- promoting activity.

Still preferred, the peptide comprises (or consists of) an amino acid sequence of SEQUENCE ID NO'S 1 , or the variant comprises (or consists of) an amino acid sequence of SEQUENCE ID NO. 3 to 80 and 84 to 1 14, wherein the peptide or variant typically has anti-inflammatory activity.

Still preferred, the peptide comprises (or consists of) an amino acid sequence of SEQUENCE ID NO'S 1, or the variant comprises (or consists of) an amino acid sequence of SEQUENCE ID NO. 3 to 80 and 84 to 1 14, wherein the peptide or variant typically cellular growth promoting activity.

Still preferred, the peptide comprises (or consists of) an amino acid sequence of SEQUENCE ID NO'S 1 , or the variant comprises (or consists of) an amino acid sequence of SEQUENCE ID NO, 3 to 80 and 84 to 1 14, wherein the peptide or variant typically has anti-aging activity. A further aspect of the current invention provides a topical composition of the invention as a medicament.

A further aspect of the current invention provides a topical composition of the invention for use in improving muscle status in a mammal.

A further aspect of the current invention provides a topical composition of the invention for use in promoting recovery of muscle, typically following exercise. A further aspect of the current invention provides topical a composition of the invention for use in maintaining or restoring muscle health (for example lean tissue mass) in a mammal.

A further aspect of the current invention provides a topical composition of the invention for use in enhancing physical performance.

A further aspect of the current invention provides a topical composition of the invention for use in treatment or prevention of a disease or condition characterised by lethargy or low energy levels.

A further aspect of the invention provides a topical composition of the invention for use in promoting gro wth of tissue.

The invention also provides a topical composition of the invention for use in promoting growth of epithelial tissue.

The invention also provides a topical composition of the invention for use in promoting growth of skin. The invention also provides a topical composition of the invention for use in promoting growth of an organ.

The invention also provides a topical composition of the invention for use in promoting growth of an organism. Preferably, the cell, tissue or organism has a normal pathology (for example ageing skin). Typically, the cell, tissue or skin has abnormal pathology (for example tissue damaged due to trauma, drug use, or epithelial tissue in the Gl tract damaged due to an inflammatory disorder).

The growth promoting uses may be in-vivo or in-vitro uses. The growth promoting uses may involve administration to mammal externally (i.e. to the skin) or internally (i.e. to the GI tract). The invention also provides a composition of the invention for use in slowing or inhibiting, or preventing ageing of human skin. Typically, administration may be by means of a plaster or patch or a formulation suitable For topical application. Another aspect of the invention provides the topical composition of the invention for use in treatment of a wound in a mammal.

Another aspect of the invention provides the topical composition for use in the treatment or prevention of a disease or condition characterised by damaged epithelial cells or tissue, and/or damaged dermal or epithelial cells or tissue, Preferably, the disease or condition is characterised by damaged dermal or epithelial cells or tissue is selected from cancer, trauma

The invention also provides a topical composition of the invention for use in maintaining or restoring gut health in a mammal.

The invention also relates to a topical composition of peptides of the invention for use in maintaining or restoring muscle health (for example lean tissue mass) in in a mammal

A further aspect of the invention provides a topical composition of the invention for use in treatment or prevention of an inflammatory disorder and/or inflammation in a mammal.

Preferably, the inflammation is symptomatic inflammation.

A still further aspect of the invention provides a topical composition of the invention for use in treatment or prevention of pain in a mammal.

Another aspect relates to a topical composition of the invention for use in treatment or prevention of a metabolic disorder in a mammal. A further aspect of the invention relates to a method of treating, preventing or caring for any one of the aforementioned and described herein diseases, conditions and/or disorders comprising a step of administering the topical composition of the invention.

The uses of the invention may be therapeutic or non-therapeutic. A further aspect of the invention relates to a topical composition comprising one or more of the peptides selected from SEQUENCE ID NO. 1 , 3 to 80, 84 to 1 14 and 120 to 1251 .

In one embodiment, the composition of the invention comprises substantially all of the peptides of SEQUENCE ID NOS 1, 3 to 80, 84 to 114 and 120 to 1251.

A further aspect of the current invention relates to a man-made treatment composition comprising the topical composition of the invention. Preferably, the treatment composition is a wound treatment composition. Preferably the treatment composition is a muscle treatment composition. Preferably, the treatment composition is an anti-aging composition. Preferably the treatment composition is an anti-inflammatory composition. In one embodiment, the composition comprises a cream, gel, lotion, rub, powder.

The invention also relates to a plaster, bandage or dressing suitable for application to the keratinous tissue or a wound and comprising the topical composition of the invention.

Preferably the topical composition or product is man-made.

Definitions All publications, patents, patent applications and other references mentioned herein are hereby incoiporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incoiporated by reference and the content thereof recited in full. Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term "a" or "an" used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. As used herein, the term "comprise," or variations thereof such as "comprises" or "comprising," are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term "comprising" is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.

As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies,

As used herein, the term "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the reduction in accumulation of pathological levels of lysosomal enzymes). In this case, the term is used synonymously with the term "therapy".

Additionally, the terms "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term "prophylaxis".

As used herein, an effective amount or a therapeutically effective amount of an agent defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement, A therapeutic result need not be a complete cure.

The term "bioactive" when used herein refers to a peptide or a peptide variant that has biological activity. For example, the biological activity may be one or more of "Glucose transport promoting" or "glucose transport promoting activity", anti-inflammatory" or "anti- inflammatory activity ⁵ ', and "growth promoting" or "growth promoting activity", or "anti- aging activity".

"Glucose transport promoting" or "glucose transport promoting activity" as applied to a peptide or variant or fragment means a peptide, variant or fragment that is capable of increasing GLUT4 translocation into skeletal muscle compared with an untreated control when employed at a concentration of 2μΜ in the following in-vitro assay, L6-GLUT4myc cells were grown in 10% FBS and 2 pg/ml blasticidin. Cells were grown for 48-72 hours before being seeded in 24- well plates at 15,000 cells per well in 2% FBS and allowed to differentiate for 6 to 8 days prior to experimentation. L6-GLUT4myc cells were serum-starved for three hours prior to incubation with 100 nM of insulin for 30mins, or 200, 20, 2.0 and 0.2 μΜ of Sl\ and 2, 1 , 0.5 and .25mg/inl of composition for 3 hours respectively, A 3 hour incubation period was selected based on previous findings identifying that incubation with branch chain amino acid containing di-pcptides for 3 hours increases glucose uptake in L6 myotubes 1. Treatments were staggered in order to determine GLUT4myc translocation at the same time point. The quantity of myc- tagged GLUT4 at the cell surface was measured by antibody-coupled colorimetric assay. Briefly, after incubation with either insulin for 30mins or synthetic peptide or protein composition for 3 hours respectively, L6-GLUT4myc cells were fixed via incubation with 3% paraformaldehyde (PFA). A 0.1 M glycine solution was then added to quench PFA and cells were blocked with 5% goat serum. The myotube monolayer was exposed to anti-myc antibody and then incubated with peroxidase conjugated donkey anti-mouse IgG. 1 niL of o- phenylenediamine dihydrochloride (OPD) reagent was added to each well and this reaction was stopped by adding 250μΙΛνβΠ of 3 M HCL. To determine GLUT4 translocation to cell surface, a measured aliquot of each condition was determined spectrophotometrically on a plate reader using absorbance at 492nm. Preferably the peptide or fragment is capable of increasing GLUT4 translocation compared with an untreated control by at least 50% (i.e a relative unit increase in GLUT4 translocation of 1 % to 1.5%).

In this specification, the term "composition" should be understood to mean something made by the hand of man, and not excludes naturally occurring compositions.

"Anti-inflammatory" as applied to a peptide, variant or fragment means a peptide, variant or fragment that is capable of significantly reducing the secretion of TNFct by LPS-stimulated J774.2 macrophages (compared with untreated I , S-stimulated J774.2 macrophages) when the macrophages are treated with ΙΟΟμΜ of the peptide, variant or fragment. J774.2 macrophages were treated with 100μΜ of synthetic peptide for 24 hours and then stimulated with (A) LPS ( l Ong/ml) for five hours or (B) LPS (l Ong/ml) for 5 hours followed by ATP (5mM) for one hour. Supernatant was collected and levels of TNFa were determined by ELISA.

"Cellular growth promoting" as applied to a peptide, variant or fragment means a peptide, variant or fragment that is eapable of increasing elastin production or cellular proliferation of human skin treated with a 20μΜ solution of peptide, variant or fragment in the following assay, Skin explants were prepared from abdominal plastic surgery. Some explants were delipidated with alcohol to obtain a dehydrated skin. These explants were maintained in maintenance medium supplied by the provider Biopredic International for 5 days. Test items are applied twice per day with 5μΤ per explant. At the end of the test, viabilities controls are realized with the MTT on two explants, the third explant is fixed in the formaldehyde 4% for histology and cell staining. For each time of analysis (Dl and D5), histologies on delipidated explants, treated explants with test items, the DMSO 0.3% control and water control, are performed.

After receipt in the laboratory, each skin explant in the maintenance medium is delipidated with 5μΙ, alcohol during 3 hours. After 3 hours, all skin explants are treated two per day with test items, and they are incubated at 37°C +/- 2°C, 5% C02 for 1 day or 5 days. Integrity of the system is realized at day 1 and day 5 with a viability control with MTT. Histology is realized by the laboratory Gredeco and the immunostaining to elastin and Ki67 are realized by the same laboratory, Immunostaining to fiiaggrin is realized by the laboratory Intertek. The detection of elastin (rabbit monoclonal antibody, clone PI 5502, LSBio) is performed using an immunoperoxidase technique two layers (ABC kit, Vector Laboratories) and revealed by AEC ( -amino- 9 -ethylcarbazole). The immunohistochemical staining intensity in the elastic fibers is evaluated using a semi-quantitative histological score, Epithelial proliferation was analyzed by immuiiohistochemistry using anti- .i67 antibody. Immunodetection was performed using an indirect immunoperoxidase technique three layers, amplified (DA O kit) and revealed by AEC (3-Amino-9-ethylcarbazole). Counting the number of labeled cells (keratinocytes of the basal layer of the epidermis) is performed and provides the total number of basal cells to calculate the % of labeled cells. The specific staining of fiiaggrin is performed with an immunoperoxidase staining (ABC kit, Fisher), The intensity of i m munoh i stochem ic al marker in the epidermis is evaluated relative to the negative control of the solvent (Water or DMSO 0.3%).

"Antibacterial" or "antibacterial activity" as applied to a peptide, variant or fragment means a peptide , variant or fragment that is capable of visibly inhibiting the growth of a bacteria in the following agar-plate based growth inhibition assay: Peptide stock=5mg/mL dissolved in DMSO. Bacterial inoculums were adjusted to McFarland 0.5 standard and MHA plates swabbed. Blank disks were placed in the plates and 10 μΐ. of each compound (at 64 ug/mL - maximum concentration tested) added. Plates were incubated at 37°C for 16- 18 hours, Appropriate controls (DMSO; Muel!er-Hinton media alone; and two antibiotic discs - ciprofloxacin and tetracycline) were also performed.

The term "topical composition" refers to a composition that is formulation for topical administration. "Topical administration" refers to the application to the keratinous tissue, such as the skin, hair and nails. Topical delivery generally means delivery to the skin, but can also mean delivery to a body lumen lined with epithelial cells, for example the lungs or airways, the gastrointestinal tract, the buccal cavity. In particular, formulations for topical delivery are described in Topical drug delivery formulations edited by David Osborne and Antonio Aman, Taylor & Francis, the complete contents of which are incorporated herein by reference, Compositions or formulations for delivery to the airways are described in O'Riordan et al (Respir Care, 2002, Nov. 47), EP2050437, WO2005023290, US2010098660, and US20070053845. Composition and formulations for delivering active agents to the ilucm, especially the proximal iluem, include microparticles and microencapsulates where the active agent is encapsulated within a protecting matrix formed of polymer or dairy protein that is acid resistant but prone to dissolution in the more alkaline environment of the ileum. Examples of such delivery systems are described in EP 1072600.2 and EP 13171757.1. An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required. Injectable forms may contain between 10-1000 mg, preferably between 10-250 mg, of active ingredient per dose. Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.

The term "cosmetic composition" when used herein relates to a composition that can be used for cosmetic purposes, personal care and/or hygiene purposes. It will be appreciated that the composition may have more than one cosmetic purpose and may be used for more than one of these purposes at the same time. A "cosmetic" when used herein can include but are not limited to, lipstick, mascara, rouge, foundation, blush, eyeliner, facial and body powder, sunscreen, sunblock, nail polish, compacts, solids, pencils.

"Pharmaceutical compositions": A further aspect of the invention relates to a pharmaceutical composition comprising a peptide of the invention or a composition of peptides of the invention, admixed with one or more pharmaceutically acceptable diluents, excipients or carriers. Even though the peptides and compositions of the present invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy. The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients, 2 ^nd Edition, (1 94), Edited by A Wade and PJ Weller. in particular, formulations for topical delivery are described in Topical drug delivery formulations edited by David Osborne and Antonio Aman, Taylor & Francis, the complete contents of which are incorporated herein by reference. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A, R. Gennaro edit. 1985). Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water. The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended ro ute of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Preservatives, stabilizers, dyes and even flavouring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of phydroxybenzoic acid. Antioxidants and suspending agents may be also used.

The term "mammal" should be understood to mean a higher mammal, especially a human. However, the term also includes non-mammalian animals such as fish. The human may be an infant, toddler, child, adolescent, adult, or elderly human. In one embodiment of the invention, the human is an elderly person, for example aged 55 or more. In one embodiment, the human is an elderly person experiencing deterioration of lean tissue mass. In one embodiment, the human is a sportsperson. In one embodiment, the human is pregnant woman. In one embodiment, the human is suffering from lethargy or perceived lack of energy.

The term "dermatologically acceptable," as used herein, means that the topical composition(s) or component(s) of the composition(s) are suitable for use in contact with human skin or keratinous tissue without risk of toxicity, incompatibility, instability and/or allergic response, and similar.

The term "sustained release" is used in a conventional sense relating to a delivery system of a compound or active, which provides the gradual release of this compound or active during a period of time and preferably, although not necessarily, with relatively constant compound release levels over a period of time. The term "peptide" used herein refers to a polymer composed of up to 50 amino acids, for example 5 to 50 amino acid monomers typically linked via peptide bond linkage. Peptides (including fragments and variants thereof) of and for use in the invention may be generated wholly or partly by chemical synthesis or by expression from nucleic acid. For example, the peptides of and for use in the present invention can be readily prepared according to well- established, standard liquid or, preferably, solid-phase peptide synthesis methods known in the art (see, for example, J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Company, Rockford, Illinois (1984), in M. Bodanzsky and A. Bodanzsky, The Practice of Peptide Synthesis, Springer Verlag, New York (1 84). When necessary, any of the peptides employed in the invention can be chemically modified to increase their stability, A chemically modified peptide or a peptide analog includes any functional chemical equivalent of the peptide characterized by its increased stability and/or efficacy in vivo or in vitro in respect of the practice of the invention. The term peptide analog also refers to any amino acid derivative of a peptide as described herein. A peptide analog can be produced by procedures that include, but are not limited to, modifications to side chains, incorporation of unnatural amino acids and/or their derivatives during peptide synthesis and the use of cross-linkers and other methods that Impose conformational constraint on the peptides or their analogs. Examples of side chain modifications include modification of amino groups, such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBILt; amidation with methylacetimidate; acctylation with acetic anhydride; carbamylation of amino groups with cyanatc, trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulfonic acid (TNBS); alkylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxy!ation of lysine with pyridoxa-5'-phosphate followed by reduction with NABHU. The guanidino group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3- butanedione, phenylglyoxal and glyoxal. The carboxyl group ma be modified by carbodiimide activation via o-acylisourea formation followed by subsequent derealization, for example, to a corresponding amide. Sulfhydryl groups may be modified by methods, such as carboxymethylation with iodoacetic acid or iodoacetamide; perfbrmic acid oxidation to cysteic acid; formation of mixed disulphides with other thiol compounds; reaction with maleimide; maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4- chloromercuribenzoate, 4-chloromercuriphenylsulfonic acid, phcnylmercury chloride, 2- chloromercuric-4-nitrophenol and other mercurials; carbamylation with cyanate at alkaline pH. Tryptophan residues may be modified by, for example, oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphonyl halides. Tryosine residues may be altered by nitration with tetranitro methane to form a 3-nitrotyrosine derivative. Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate. Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3-hydroxy-5- phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thienyl alanine and/or D- isomers of amino acids. Peptide structure modification includes the generation of retro-inverso peptides comprising the reversed sequence encoded by D-amino acids.

A "variant" of the peptide shall be taken to mean a peptide having an amino acid sequence that is substantially identical to SEQUENCE ID NO.l, but which is altered in respect of one or more amino acid residues. Preferably such alterations involve the insertion, addition, deletion and/or substitution of 11 or fewer amino acids, more preferably of 10 or fewer, 9 or fewer, 8 or fewer, 7 or fewer, 6 or fewer, preferably 5 or fewer, 4 or fewer, even more preferably of 3 or fewer, most preferably of 1 or 2 amino acids only. Insertion, addition and substitution with natural and modified amino acids is envisaged. The variant may have conservative amino acid changes, wherein the amino acid being introduced is similar structurally, chemically, or functionally to that being substituted. Generally, the variant will have at least 70% amino acid sequence identity, preferably at least 80% sequence identity, more preferably at least 90% sequence identity, and ideally at least 95%, 96%, 97%, 98% or 99% sequence identity with the parent sequence.

The term variant is also taken to encompass the term "fragment" and as such means a segment of amino acid SEQUENCE ID NO. 1. Typically, the fragment has between 3 and 13 contiguous amino acids in length. Generally, the fragment has a charge of -5 to +3. The charge of a peptide, fragment or region is determined using the method of Cameselle, J.C., Ribeiro, J.M., and Si!lero, A. (1986), Derivation and use of a formula to calculate the net charge of acid-base compounds. Its application to amino acids, proteins and nucleotides. Biochem. Educ. 14, 131 - 136. In this specification, the term "sequence identity" should be understand to comprise both sequence identity and similarity, i.e. a variant (or homolog) that shares 70% sequence identity with a reference sequence is one in which any 70% of aligned residues of the valiant (or homolog) are identical to, or conservative substitutions of, the corresponding residues in the reference sequence across the entire length of the sequence. Sequence identity is the amount of characters which match exactly between two different sequences. Hereby, gaps are not counted and the measurement is relational to the shorter of the two sequences.

In terms of "sequence homology", the term should be understood to mean that a variant (or homolog) which shares a defined percent similarity or identity with a reference sequence when the percentage of aligned residues of the variant (or homolog) are either identical to, or conservative substitutions of, the corresponding residues in the reference sequence and where the variant (or homolog) shares the same function as the reference sequence.

This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example, one alignment program is BLAST, using default parameters. Details of these programs can be found at the following Internet address: http://www.ncbi.nlm.nih.gov/blast/Blast.cgi. "Inflammatory disorder" means an immune-mediated inflammatory condition that affects humans and is generally characterised by dysregulatcd expression of one or more cytokines. Examples of inflammatory disorders include skin inflammatory disorders, inflammatory disorders of the joints, inflammatory disorders of the cardiovascular system, certain autoimmune diseases, lung and airway inflammatory disorders, intestinal inflammatory disorders. Examples of skin inflammatory disorders include dermatitis, for example atopic dermatitis and contact dermatitis, acne vulgaris, and psoriasis. Examples of inflammatory disorders of the joints include rheumatoid arthritis. Examples of inflammatory disorders of the cardiovascular system are cardiovascular disease and atherosclerosis. Examples of autoimmune diseases include Type 1 diabetes, Graves disease, Guillain- arre disease, Lupus, Psoriatic arthritis, and Ulcerative colitis. Examples of lung and airway inflammatory disorders include asthma, cystic fibrosis, COPD, emphysema, and acute respiratory distress syndrome. Examples of intestinal inflammatory disorders include colitis and inflammatory bowel disease. Other inflammatory disorders include cancer, hay fever, periodontitis, allergies, hypersensitivity, ischemia, depression, systemic diseases, post infection inflammation and bronchitis. The peptides and compositions of the invention may also be employed in the non- therapeutic treatment of inflammation. Examples of non-therapeutic treatment of inflammation include use to relieve normal, non-pathological, inflammation, for example inflammation in the muscles and joints following exercise.

In this specification, the term "Metabolic disorder" should be understood to include prediabetes, diabetes; Type- 1 diabetes; Type-2 diabetes; metabolic syndrome; obesity; diabetic dyslipidemia; hyperlipidernia; hypertension; hypertriglyceridemia; hyperfattyacidemia; hypcreholerteroleinia; hyperinsulinemia, and MODY.

"Ani-ageing" means inhibiting or slowing the appearance of ageing of a human's skin and/or reversing the appearance of ageing. "Slowing or inhibiting ageing of the skin" means slowing or Inhibiting the ageing process in the skin, and/or reversing the appearance of ageing. "Disease or condition characterised by damaged dermal or epithelial cells or tissue" means any condition or disease that results in damaged dermal or epithelial tissue or cells or organs. One example is trauma which often results in damaged skin. Another example is an inflammatory skin condition such as psoriasis or exeezma which often results in damaged skin. Another example is an inflammatory disorder of the lower intestines which can result in damaged epithelial cells/tissue lining the lower intestines. Another example is damaged epithelial cells/tissue lining the lower intestines caused by ingestion of a toxic or damaging substance, for example toxic chemicals or drugs. Another example is cancer, for example bowel cancer, which can result in damaged epithelial tissue in the bowel. Another condition is a peripheral inflammatory disorder such as atopic dermatitis which can result in damage to the skin in humans.

"Disease or condition characterised by bacterial infection" means any condition or disease characterised having a pathology caused by growth of bacteria or by bacterial infection, including for example MRSA, salmonella, listeria, bacterial pneumonia. Staphylococcal food poisoning, bacterial memingitis. Specific examples are provided in https;/'/en.wikipedia.org/wiki/Lisl of infectious diseases.

"Man-made" as applied to comestible products should be understood to mean made by a human being and not existing in nature.

"Improving muscle status" means improving the muscle health, for example promoting skeletal muscle protein synthesis, skeletal glucose absorption, improving lean tissue mass in therapeutic or non-therapeutic context, promoting muscle recovery generally after activity exercise, or improving muscle performance. The methods or uses may be therapeutic or non-therapeutic. The term "improving lean tissue mass status" should be understood to mean increasing lean tissue mass, or inhibiting or preventing the rate of lean tissue mass degradation.

"Promoting muscle recovery" means causing an increase in absorption of glucose in skeletal muscle compared with untreated skeletal muscle.

"Disease or condition characterised by lethargy or low energy levels" means any condition or disease characterised by a feeling or tiredness or low energy. Examples include allergies. asthma, anemia, cancer and its treatments, chronic pain, heart disease, infection, depression, eating disorders, grief, sleeping disorders, thyroid problems, medication side effects, alcohol use, or drug use. "Maintaining or restoring muscle health" means helping retain or restore mammalian muscle health resulting from damage incurred during exercise. By promoting glucose transport in skeletal muscle the peptides promote recovery from exercise, and relieve muscle soreness/pain and injury connected with exercise. They can also be used to decrease and prevent muscle cramping, and to allow a faster recovery from muscle cramping. Cramping can result from physical stress, mental stress, and or Repetitive Strain Injury stress. By promoting glucose transport the peptides help reduce Myopathy of the muscle, and help prevent Sarcopenia in mammals, promote recovery fi-om injuries during exercise, and relieve muscle soreness/pain and injury connected with exercise. The invention also relates to a peptide or composition of the invention for use in maintaining or restoring muscle health in a mammal.

In this specification, the term "personal care product" should be understood to mean a composition formulated for use by humans in cleaning or treating the human body, particularly the skin, teeth, nails, feet and hair. Examples include shampoo, conditioner, skin creams and lotions, powders, dentifrice, shower gel or creams, bath or shower gel, hair dye, soap, body scrub, exfoliant, anti-dandruff solutions body lotion, shaving solutions, moisturisers, cleaners, masks, oils, serums, and rinses, deodorant, and anti-perspirant.

The term "skin aging" is used in the sense in which it is generally and widely used in the art of cosmetic and personal care products. Signs of skin aging include wrinkles, lines, crevices, bumps, red spots, large pores, roughness, dullness, loss of elasticity, sagging, loss of tightness, discoloration, blotching, hyperpigmentation, freckles, keratosis, inflammation, collagen breakdown and other histological changes in the skin layers including underlying tissue.

The term "cosmetically or pharmaceutically acceptable salts" means a salt recognized for its use in animals and more specifically in human beings, and includes salts used to form base addition salts, either they are inorganic, such as and not restricted to, lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminium among others, either they are organic, such as and not restricted to, ethylamine, diethylamine, ethylenediamine, ethanolamine. diethanolaminc, arginine, lysine, histidine or piperazine among others, or acid addition salts, either they are organic, such as and not restricted to, acetate, citrate, lactate, rnalonaie, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate among others, or inorganic, such as and not restricted to, chloride, sulfate, borate or carbonate, among others. The nature of the salt is not critical, provided that it is cosmetically or pharmaceutically acceptable. The cosmetically or pharmaceutically acceptable salts of the peptides of the invention can be obtained by the conventional methods, well known in the prior art [Bcrge S. M. et a!., "Pharmaceutical Salts", J. Pharm. Sci., (1977), 66, 1 -19].

The term "natural" as applied to a peptide means a peptide that includes (a) a fragment of a plant protein, typically rice or pea protein, or variants of pea protein including lentil, sweet pea, or chick pea or variants of rice protein including oat, grass, corn, wild rice and bananas, or (b) a variant of the fragment of a plant protein, for example a glucose transport promoting fragment of a homolog of the plant protein. The peptides or fragments of the invention may be isolated from plant protein composition or made synthetically using methods known to a person skilled in the art and described herein.

"C-terminal domain" as applied to a fragment means the first three amino acids at the c- terminus of the fragment. "N-terminal domain" as applied to a fragment means the last three amino acids at the n- terminus of the fragment,

"Homolog" of a reference protein should be understood to mean a protein from a different species of plant having at least 60%, 70%, 80%, 90%, 1%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence homology with the reference protein. Thus, for example, homologs of pea protein PI 3 18 include:

hydro

>gi| 137584|sp|P08438.1 |VCL_V!CFA RecName: Full-Vicilin; Flags: Precursor [Vicia faba] >gi|22057|emb|CAA68559.11 vicilin [Vicia faba ar. minor] >gi|38393 1031 |gb|AFH56916.11 vicilin [Vicia faba] SEQ ID 81

>gi|502105533|refjXP_004492829.11 PREDICTED: vicilin-like isoform X I [Cicer

arietmum] ChickPea SEQ ID 82

>gi|29539109|cmb|CAD87730.11 allergen Len c 1 ,0101 [Lens culinarls] Lentil SEQ ID 83 In the specification the terms "comprise, comprises, comprised and comprising" or any variation thereof and the terms "include, includes, included and including" or any variation thereof are considered to be totally interchangeable and they should all be afforded the widest possible interpretation and vice versa. Brief Description of the Drawings

The invention will be more clearly understood from the following description of an embodiment thereof, given by way of example only, with reference to the accompanying drawings, in which: -

Figure 1 illustrates the effect of SP2 on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells. L6-GLUT4myc cells were serum starved for 3 hours and then treated with either 200, 20, 2 and 0.2 μΜ of each synthetic peptide for 3 hours or 100 nM of insulin for 30 minutes.

Data are presented as average of triplicates.

Figure 2 illustrates the effect of SEQ ID No. 1 on glucose uptake.

Detailed Description of the Drawings

In the broadest sense, the first aspect of the invention provides a topical cosmetic or pharmaceutical composition (hereafter "topical composition of the invention") comprising a cosmetically or pharmaceutically effective amount of a peptide comprising an amino acid sequence of SEQUENCE ID NO. 1 or a variant thereof (hereafter "peptide of the invention").

SEQUENCE ID NO.l

VLDLAIPVNRPGQL

The specific pea protein from which the natural (glucose transport promoting fragment) peptide of the invention is derived is provided in SEQUENCE ID NO: 2 (Pea Protein 1 - PI 391 8). Homologs of Pea Protein 1 (SEQUENCE ID NO: 2) include Vicia fabki, Cicer arietinum and Lens culinans homologs (SEQ ID NO: 81 to 83).

>gi| 137584|sp|P08438.1 |VCL_VICFA RecName: Full=Vicilin; Flags: Precursor [Vicia faba] >gi|22057|emb|CAA68559.1 | vicilin [Vicia faba var. minor] >gi|38393 10 1 |gb|AFH56916.1 1 vicilin [Vicia faba]

SEQUENCE ID NO. 81

MAATTL DSFPLLTLLGIAFLASVCLSSRSDQDNPFVFESNRFQTLFENENGHIRLLQK FDQHS LLENLQNYRLLEYKSKPHTIFLPQQTDADFILVVLSGKAILTVLLPNDRNSFS

LERGDTI LPAGTIGYLVNRDDEEDLRVLDLVIPVNRPGEPQSFLLSGNQNQPSILSGF SKNILEASFNTDYKEIE VLLEEHG EKYHRRGLKD RQRGQEENVIV ISRKQIEEL NKNA SSSKKSTSSESEPFNLRSREPIYSNKFG FFEITPKRNPQLQDLNIFVNYVEINE GSLLLPHY SRAIVIVTV EGKGDFELVGQRNENQQGLREEYDEEKEQGEEEIRKQV QNYKAKLSPGDVLVIPAGYPVAIKASSNLNLVGFGI AENNQ YFLAGEEDNVISQIH KPVKELAFPGSAQEVDTLLENQ QSHFANAQPRERERGSQEIKDHLYSILGSF [SEQ ID 81]

>gi|502105533 |ref|XP_004492829.1 j PREDICTED: vicilin-likc isoform X I [Cicer arietinum] ChickPca

SEQUENCE ID NO. 82

MAIKARFPLLVLLGIVFLASVCA SDKENPFFF SNNCQTLFENENGHVRI .I.QRFDK RSQLFENLQNYRLMEYNSKPHTLFLPQFINDADFILVVLRGRAILTVLNPNDRNTFKL ERGDTIKLPAGTIAYLANRDDMEDLRVLDLAIPVNRPGQFQSFSLSGNENQQSYFQGF

SKKILEASFNSDYEEIERVLLEEQEQKPEQRRGHKGRQQ5QETDVIVKISREQIEEL SK NAKSNCKKSVSSESEPFNLRSRSPIYSNRFGNFFEITPEKNPQL DLDIFVNSVEIKEGS LLLPHFNSRATVILVVNEGKGEVELVGLRNENEQEN KEDEEEEEDRNVQVQRFQS LSSGDVVVIPASHPFSINASSDLFLLGFGINAQNNQR FLAGEEDNVISQIQRPVKEV AFP GS AEE VDRLLKNQRQ SHF ANAQPQQKRKGS QRIRSPF [SEQ ID 82] >gi|29539109jembjCAD87730. il allergen Len c 1.0101 {Lens culinarisj Lentil

SEQUENCE ID NO, 83

SRSDQENPFIFKSNRFQTIYENENGHIRLLQRFD RSKIFENLQNYRLLEYKSKPFITIFL PQFTDADFILVVLSGKAILTVLNSNDRNSFNLERGDTI LPAGTIAYLANRDDNEDLR VLDLAIPVNRPGQLQSFLLSGTQNQPSFLSGFSKNILEAAFNTEYEEIE VLLEEQEQK S QHRRSLRD RQE ITNED VI VKV SREQIEEL S KNA S SS KS VS SESE PFNLRSRNPI YS NKFGKFFEITPE PQLQDLDIFVNSVEIKEGSLLLPNYNSRAIVIVTVNEGKGDFELV GQRNENQQEQREENDEEEGQEEETTKQVQRYRARLSPGDVLVIPAGHPVAINASSDL NLIGFGINAK QRNFLAGEEDNVISQIQRPVKELAFPGSSREVDRLLTNQKQSHFAN

AQPLQIE [SEQ ID 83]

SEQUENCE ID NO. 2

MAATT KASFPLLM LMGISFLASVCVSSRSDPQNPFIF SN KFQTLFENENGHIRLLQ FDQRSKIFENLQ NYRLLEYKSKPHTI FLPQHTDADYILVVLSGKAILTVLKPDDRNSFN LERGDTIKLPAGTIAYLVNRDDNEEI . RVLDLA!PVNRPGQLQSFLLSGNQNQQNYLSGFSKNi LEASF NTDYEEIEKVLLEEH EKETQHRRSLKDKR QQSQEENV!VKLSRGQIEELS NAKSTSKKSVSSESEPFNLRSRGPIYSN EFGKFFEITPE N PQl QDLDfFV NSVEIKEGSLLLPHYNSRAIVIVTVNEGKGDFELVGQRNENQQEQRKEDDEEEEQGEEE! N QVQNYKAK LSSGDVFVIPAGHPVAVKASSN LDLLGFGINAENNQRN FLAGDEDNVIS iQRPVKELAFPGSAQEVDRI L ENQKQSHFADAQPQQRERGSRETRDRLSSV

In one embodiment of the invention, the peptide or variant is bioactive. In one embodiment, the peptide or variant has glucose transport promoting activity. In an embodiment, the peptide or variant has anti-inflammator activity. In one embodiment, the peptide or variant has cellular growth promoting activity. In one embodiment, the peptide or variant has anti-aging activity. It will be appreciated that the peptide or variant may have two or three of anti-inflammatory activity, glucose transport promoting activity, cellular growth promoting activity and anti- aging activity. The peptide or variant may have anti-inflammatory activity, glucose transport promoting activity, cellular growth promoting activity and anti-aging activity.

In an embodiment of the invention the peptide comprises from about 3 to 50 amino acids in length, about 14 to about 50 amino acids in length, preferably about, 15, 20, 25, 30, 35, 40, 45, or 49 amino acids in length, preferably about 14, 15, 16, 17, 18, 19, or 20 amino acids in length.

In an embodiment of the invention the variant comprises from about 3 to about 14 amino acids in length, preferably about, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13 amino acids in length.

In one embodiment, the variant has 1 to 5 amino acid changes compared to SEQUENCE ID NO; 1. In one embodiment, the variant has 1 to 4 amino acid changes compared to SEQUENCE ID NO: 1. In one embodiment, the variant has 1 to 3 amino acid changes compared to SEQUENCE ID NO: 1. In one embodiment, the variant has 1 to 2 amino acid changes compared to SEQUENCE ID NO: 1. In one embodiment, the amino acid change is an amino acid substitution. In one embodiment, the amino acid substitution is a conservative substitution. In one embodiment, the amino acid change is an amino acid addition. In one embodiment, the amino acid change is an amino acid deletion.

The variants of the invention include:- Variants of SEQUENCE ID NO: 1 (peptide E64 SP2

Variants of SEQUENCE ID NO: 1 (VLDLAiPVNRPGQL) including variants having 1 ,2 or 3 conservative amino acid substitutions, 1 , 2 to 3 non-conservative amino acid substitutions, 1 -2 amino acid additions, 1 , 2 or 3 amino acid deletions, are provided below: One conservative amino acid substitution:

ILDLAIPVNRPGQL (SEQ ID 3); VLELAIPVNRPGQL (SEQ ID 4); VLDLAVPVNRPGQL (SEQ ID 5); VLDLAIPINRPGQL (SEQ ID 6); VLDLAIPVNRPGQL (SEQ ID 7); VLDLAIPVEKPGQL (SEQ ID 8); VLDL A IP VNKP GEL (SEQ ID 9) Two conservative amino acid substitutions:

ILELA1PVNRPGQL (SEQ ID 10; ILDLAVPVNRPGQL (SEQ ID 1 1); VLELAVPVNRPGQL (SEQ ID 12); VLELAIPVNKPGQL (SEQ ID 13); ILDLAIPVNKPGQL (SEQ ID 14); VLDLAVPVNKPGQL (SEQ ID 15); VLDLAIPVEKPGEL (SEQ ID 16); ILDLAIPVNKPGEL (SEQ ID 17); VLELAIPVEKPGQL (SEQ ID 18).

Three conservative amino acid substitutions:

ILELAVPVNRPGQL (SEQ ID 19); ILELAIPVNKPGQL (SEQ ID 20); VLELAVPVNKPGQL (SEQ ID 21 ); ILELAIPVNRPGEL (SEQ ID 22); ILDLAIPVNKPGEL

(SEQ ID 23); VLDLAVPVEKPGQL (SEQ ID 24); VLDLAVPVERPGEL (SEQ ID 25); VLELAIPVERPGEL (SEQ ID 26).

One non-conservative amino acid substitution

KLDLAIIVNRPGQL (SEQ ID 27); VLDLAIPVNRPGQK (SEQ ID 28); VLDLAIPVNRPGQL (SEQ ID 29); VLDLAIPVNRPGQL (SEQ ID 30);;

VLDLAIPVNRPCQL (SEQ ID 3 1); VLDLWIPVNRPGQL (SEQ ID 32); VLDLAIPVNRPGQL (SEQ ID 33); VLYLAIPVNRPGQL (SEQ ID 34). Two non-conservative amino acid substitution

VLDL YIP V GRPGQL (SEQ ID 35); VKDLAIPWNRPGQL (SEQ ID 36); VLDLAIPVNRPCCL (SEQ ID 37); VLDLAGGVNRPGQL (SEQ ID 38); VLDLAIPKNEPGQL (SEQ ID 39); PLDLAIPVNDPGQL (SEQ ID 40); VLDLAIPVNRPIQL (SEQ ID 41); VLDHAIPVNRPGQL (SEQ ID 42)

Three non-conservative amino acid substitution

VLDLAIPVNRPGGG (SEQ ID 43); VLDLI IIPGNEPGQL (SEQ ID 44); VYKLAIPVNEPGQL (SEQ ID 45); VLDLAIPVNRPYPG (SEQ ID 46); VLDYAIPKNDPGQL (SEQ ID 47); VLDLAIPVNRPGQL (SEQ ID 48); RRRLAIPVNRPGQL (SEQ ID 49); VLDLAIGVNRGPQL (SEQ ID 50)

One or two amino acid additions

VLDLAIPVNRPGFQL (SEQ ID 51); VLDLADIPVNRPGQL (SEQ ID 52); VLDLAIPVGNRPGQL (SEQ ID 53); VLQQDLAIPVNRPGQL (SEQ ID 54); VLDLAIPVNRGPGQKL (SEQ ID 55); VLDGLPLAIPVN PGQL (SEQ ID 56); V LDLAI P VN RPG QLLL (SEQ ID 57); VLDLFLG AIP VNRPGQL (SEQ ID 58)

One, two or three amino acid deletions

VLDLAIPVNRGQL (SEQ ID 59); VLDLAPVNRPGQL (SEQ ID 60); LDLAIPVNRPGQL (SEQ ID 61); VLDLAIPVNRPGQ (SEQ ID 62); DLAIP VNRPGQL (SEQ ID 63); VLDLAIPVNRPG (SEQ ID 64); V LD L A INRPGQL (SEQ ID 65); VLDAIVNPGQL (SEQ ID 66) The variant may be a bioactive variant. In one embodiment, the variant is a glucose transport promoting variant. In one embodiment, the variant is an anti-inflammatory variant. In one embodiment, the variant is an anti-aging variants. In one embodiment, the variant has cellular growth promoting activity. It will be appreciated that in one embodiment the bioactive variant is two or more of glucose transport promoting variant, an anti-inflammatory variant, cellular growth promoting variant and an anti-aging variant. In one embodiment, the bioactive variant is a glucose transport promoting variant, cellular growth promoting variant, an antiinflammatory variant and an anti-aging variant.

The invention also provides fragments of SEQ ID NO No. 1 , and peptides comprising one or more of these fragments.

These fragment may be a bioactive fragment. In one embodiment, the fragment is a glucose transport promoting fragment. In one embodiment, the fragment is an anti-inflammatory fragment. In one embodiment, the fragment has cellular growth promoting activity. In one embodiment, the fragment is an anti-aging fragment. It will be appreciated that in one embodiment the bioactive fragment is two or more of glucose transport promoting fragment, an anti-inflammatory fragment, cellular growth promoting fragment and an anti-aging fragment. In one embodiment, the bioactive fragment is a glucose transport promoting fragment, an anti-inflammatory fragment, cellular growth promoting fragment and an anti- aging fragment.

In one embodiment, the fragments are glucose transport promoting fragments. Examples of fragments of SEQ ID NO: 1 are provided below: VLDLAIPVNRPGQ (SEQ ID 67); VLDLAIPVNRPG (SEQ ID 68); VLDLAIPVNRP (SEQ ID 69); LDLAIPVNRPGQL (SEQ ID 70); DLAIPVNRPGQL (SEQ ID 71 ); LAIPVNRPGQL (SEQ ID 72); LDLAIPVNRPGQ (SEQ ID 73); DLAIPVNRPG (SEQ ID 74); LAIPVNRP (SEQ ID 75); VLDLAIPVN (SEQ ID 76); AIPVNRPGQL (SEQ ID 77); VNRPGQL (SEQ ID 78); VLDLAIPV (SEQ ID 79), and VLDLAIPVNR (SEQ ID 80),

Examples of peptides of the invention are as follows:

VLDLAIP VNRPGQL Q (SEQ ID 84); VLDLAIPVNRPGQLQSF (SEQ ID 85), VLDLAIP VNRPGQLQ S F(SEQ ID 86); VLDLAIP VNRPGQLQ (SEQ ID 87);

VLDLAIPVNR (SEQ ID 88); VLDLAIPVNR(SEQ ID 89); VLDLAIPVNR (SEQ ID 90);

LAIPVNRPGQLQSFL (SEQ ID 91); LAIPVNRPGQ (SEQ ID 92); DLAIPVNRPGQLQSF

(SEQ ID 93); LAIPVNRPGQLQSF (SEQ ID 94); LAIPVNRPGQLQS (SEQ ID 95);

VLDLAIP VNRPGQLQ (SEQ ID 96); DLAIP VNRPGQLQ (SEQ ID 97); LAIPVNRPGQLQ (SEQ ID 98); LAIPVNRPGQL (SEQ ID 99); DLAIPVNRPGQL (SEQ ID 100);

DLAIP VNRPGQLQS (SEQ ID 101); LAIPVNRPGQLQSFLLSG (SEQ ID 102);

LAIP VNRPG QLQSFLLS GNQNQ (SEQ ID 103); LDLAIPVNRPGQL (SEQ ID 104);

LAIPVNRPGQLQSFLL (SEQ ID 105); LAIPVNRPGQLQSFLLS (SEQ ID 106);

VLDLAIPVNRPGQLQSF (SEQ ID 107); VLDLAIPVNR(SEQ ID 108); LAIPVNRPGQLQSFLLSG (SEQ ID 109); LDLAIPVNRPGQL (SEQ ID 1 10);

V LD LAIP NRPGQLQ (SEQ ID 1 1 1 ); LAIPVNRPGQLQSFLLSGNQNQ (SEQ ID 112);

AIPVNRPGQLQSF (SEQ ID 1 13); AIP VNRPGQLQS (SEQ ID 1 14).

It will be appreciated that the topical composition may comprise a plurality of peptides, fragments and/or variants. In one embodiment, the topical composition comprises substantially all the peptides. In one embodiment, the topical composition comprises substantially all the variants.

In one embodiment, the topical or cosmetic composition is substantially free of other peptides.

The topical composition of the invention may be presented in a formulation selected from the group comprising creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balsams, foams, lotions, gels, cream gels, hydro-alcoholic solutions, hydro-glycolic solutions, cosmetic, personal, care product, hydrogels, liniments, sera, soaps, dusting powder, paste, semi solid formulations, liniments, serums, shampoo, conditioner, ointments, any rinse off formulation, talc, mousses, powders, sprays, aerosols, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, patches, gel patches, bandages, an adhesive system, water-in-oil emulsions, oil-in- water emulsions, and silicone emulsions.

In an embodiment of the current invention, the emulsion contains a lipid or oil, The emulsion may be, but is not limited to, oil-in-water, water-in-oil, water-in-oil-in- water and oil-in-water- in-silcone emulsions, The emulsion may contain a humectant. The emulsion may contain an anti-foaming agent, such as silicone. The emulsion may have any suitable viscosity. Emulsions may further contain an emulsifier and/or an anti-foaming agent, Methods of preparing an emulsion are known to a person skilled in the art.

The topical composition of the invention may be incorporated into a medical device for administration. Such a device can include but is not limited to a fabric, patch, bandage, gauge, sock, tight, underwear, dressing, glove, mask, adhesive patches, non-adhesive patches, occlusive patches and microelectric patches or suitable adhesive system. In such an embodiment, the device is in direct contact with the keratinous layer such as the skin, thus releasing the peptides of the invention, It will be understood that the topical composition may be incorporated in any suitable form as detailed herein. For example, the topical composition or peptides of the invention can be incorporated into the device or be present on the surface of the device or can be in a cream, gel or wax formulation or any suitable formulation defined herein and incorporated into the device or on the surface of the device.

The device may be adapted for adhesion or attachment to the skin.

In one embodiment the device is adapted to release a constant quantity of the composition or the peptides of the invention. It will be understood that the amount of the composition contained in the sustained release system will depend, for example, on where the composition is to be administered, the kinetics and duration of the release of the composition of the invention, as well as the nature of the condition, disorder and/or disease to be treated and/or cared for. The device may be such that the composition is released by biodegradation of the device, or by friction between the device and the body, due to bodily moisture, the skin's pH or body temperature.

In an embodiment of the invention the topical composition may further comprise at least one cosmetically or pharmaceutically acceptable excipient. Excipient may be used interchangeabl with, functional ingredient or additive. It will be understood that although the topical compositions of the current invention can be administered alone, they will generally be administered in admixture with a cosmetic or pharmaceutical excipient. Cosmetically or pharmaceutically acceptable excipient are well known in the art and any known excipient, may be used provided that it is suitable for topical administration and is dermatologically acceptable without undue toxicity, incompatibility and/or allergic reaction.

Preferably any excipient included is present in trace amounts. The amount of excipient included will depend on numerous factors, including the type of excipient used, the nature of the excipient, the component(s) of the topical composition, the amount of active or peptide in the topical composition and/or the intended use of the topical composition. The nature and amount of any excipient should not unacceptably alter the benefits of the peptides of this invention.

In an embodiment of the invention the excipient may be a suitable diluent, carrier, binder, lubricant, suspending agent, coating agent, preservative, stabilisers, dyes, vehicle, solubilising agent, base, emollient, emulsifying agent, fragrance, humectant, and/or surfactants. Examples of suitable diluents include, but are not limited to, any diluent disclosed in disclosed in US2014120131 or US20041 32667. Examples include ethano). glycerol and water.

Examples of suitable carriers include, but are not limited to, lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and any suitable carrier disclosed in US2014120131 or US2004132667. Examples of suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxy methyl cellulose and polyethylene glycol and any suitable binder disclosed in US2014120131 or US2004132667.

Examples of suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride and any suitable lubricant disclosed in US2014120131 or US2004132667.

The carrier may be any suitable carried known in the art or disclosed in US2014120131 or US2004132667. In some embodiments, the carrier may include, but is not limited to, a liquid, such as water, oils or surfactants, including those of petroleum, animal, plant or synthetic origin, polymer, oil, such as peanut oil, mineral oil, castor oil, soybean oil, alcohol, polysorbates, sorbitan esters, ether sulfates, sulfates, bctaines, glycosides, maltosides, fatty alcohols, nonoxynols, poloxamers, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, or digitonin. It will be understood that the carrier will be dermato!ogically acceptable. Preferred carriers contain an emulsion such as oil-in-water, water-in-oil, water-in-oil-in-water and oil- in- watcr-in-siliconc emulsions. Emulsions may further contain an emulsifier and/or an antl- foaming agent. in. an embodiment of the invention, the topical composition may further comprise one or more additional ingredients. The topical composition of the invention may be administered consecutively, simultaneously or sequentially with the one or more other additional agents. Such additional ingredients may be those of benefit to include in a topical composition, or of benefit depending on the intended use of the topical composition. The additional ingredient may be active or functional or both.

Examples of such additional ingredients include, but are not limited to, one or more of cleaning agents, conditioning agents, sunscreen, pigment, moisturiscr, thickening agents, gelling agents, essential oil, astringents, pigments, anti -caking agent, anti-foaming agent, binders, additives, buffers, chelating agents, external analgesics, film formers or materials, bulking agents, polymers, opacifying agents, pH adjusters, propellants, reducing agents, sequestrants, skin bleaching and lightening agents, skin conditioning agents, a!oe vera, healing agents, soothing agents, smoothing agents, pantothenic acid, treating agents, thickeners, vitamins, colourants, pharmaceuticals, antiseptic agents, antifoaming agents, buffering agents, astringents, polymers, pH adjuster, deodorant or any other dermatologically acceptable carrier or surfactant.

It is to be understood that additional ingredients listed may provide more than one benefit. The classification given herein is for clarity and convenience only and not intended to limit the additional ingredient to that particular application or category listed. Any additional ingredients should be suitable for application to the skin without undue toxicity, incompatibility and/or allergic reaction.

In some embodiments, the additional ingredient has glucose transport activity or aids glucose transport activity. In some embodiments, the additional ingredient has anti-inflammatory activity or aids anti-inflammatory activity. In some embodiments, the additional ingredient has anti-aging activity or aids anti-aging activity. In some embodiments, the additional ingredient is for keratinous layer health and/or development, skin health and/or development, and/or muscle health, recovery and/or development. The active agent may be a pharmacological enhancer. Such active agents are known and available on the market. In such cases, the topical composition of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.

In some embodiments, the additional ingredient may be farnesol ([2E, 6E], -3, 7, 1 1 ,-trimethyi- 2, 6, 10, dodecatrien-l -ol), phytantriol (3, 7, 1 1 , 15, tetramethylhexadecane-1 , 2, 3, -triol), desquamation actives, enzymes, enzyme inhibitors, enzyme activators, botanical extracts and marine extracts, anti-acne actives, anti-wrinkle or anti atrophy actives, anti-oxidant/radical scavengers, chelators, flavonoids, anti-inflammatory agents, anti-cellulite agents, topical anaesthetics, tanning actives, skin lightening agents, skin healing agents, bisabolol, antimicrobial or antifungal active, sunscree actives, particulate material, conditioning agents, structuring agents, thickening agent,

The desquamation active may be any suitable agent that enhances the skin appearance or texture of the skin and is as disclosed in US20141201 31 or 1JS2004132667.

Examples of anti-acne actives are as disclosed in US20141201 31 or US2004132667 and include, resorcinol, salicylic acid, erythromycin, zine, sulfur, benzoyl peroxides.

Examples of thickening agents are as disclosed in US2014120131 or US2004132667 and include carbox lic acid polymers, crosslinked poly aery late polymers, polyacrylamide polymers, polysaccharides.

Examples of conditioning agents are as disclosed in US2014120131 or US2004132667 and include humcctants, moisturiser or skin conditioner.

Examples of structuring agents are as disclosed in US201412013 1 or US2004132667 and include any agent that provide rheological characteristics to the composition and contributes to the stability of the composition.

Any suitable antimicrobial or antifungal active may be used and examples are as disclosed in US2014120131 or US2004132667. Such actives are capable of destroying microbes, preventing growth or action of microbes. Examples include but are not limited to β-iactam drugs, quinolone drugs, tetracycline, erythromycin, streptomycin sulfate, salicylic acid, benzoyl peroxide.

Examples of a particulate material include metallic oxide. Examples of anti-cellulite agents include xanthine agents. Examples of tanning actives includes 1, 3-dihydroxy-2-propanone and those disclosed in US2014120131 or US2004132667,

Examples of topical anaesthetics include benzocaine, lidocaine and bupivacainc and those disclosed in US201412013 1 or US20041 2667. Examples of skin lightening agents include any agent known in the art such as kojic acid, ascorbic acid and those disclosed in US2014120131 or US2004132667.

Examples of sunscreen actives include any suitable organic or inorganic sunscreen active. Examples include metallic oxides, 2-ethylhexyl-p-mcthoxycinnamate and those disclosed in US2014120131 or US2004132667. Examples of skin healing agents includes panthenoic acid as disclosed in US2014120131 or US2004132667.

Examples of anti-inflammatory agents include any agent that enhances the skin appearance, tone or colour and include but are not limited to corticosteroids, hydrocortisone, non-steroidal agents such as ibuprofen and aspirin and those disclosed in US2014120131 or US2004132667. Examples of flavonoids includes flavanones, methoxy flavonones, unsubstituted chalcone and mixtures thereof and those disclosed in US2014120131 or US2004132667.

Examples of enzymes include lipases, proteases, catalase, super oxide-dismutase, amylase, peroxidase, glucuronidase, ceraniidases, hyaluronidases. Examples of enzyme inhibitors include trypsine inhibitors, Bowmann Dirk inhibitors, chymotrypsin inhibitors, botanical extracts, flavonoids, quercetin chalcone and those disclosed in US2014120131 or US2004132667 and mixtures thereof. Examples of enzyme activators include coenzyme A, Q10 (ubiquinone), glycyrrMzin, berberine, chrysin and those disclosed in U52Q14120131 or US2004132667 and mixtures thereof

Examples of anti-winkle or anti atrophy actives include sulfur containing D and L amino acids, particular, N-acyl derivatives such as N-aeetyl-1 , -cysteine, hydroxyl acids, phytic acid, lipoic acid, lysophosphatidic acid, skin peel agents, vitamin Bj, retinoids and those disclosed in US2014120131 or US2004132667 and mixtures thereof.

The anti-oxidant/radical scavenger agent may be any agent that is useful for providing protection against UV radiation or other environmental agents which may cause skin damage such as those disclosed in US2014120131 or US2004132667. Examples of anti-oxidant/radical scavengers include ascorbic acid, its salts and derivatives (vitamin C), tocopherol its salts and derivatives (vitamin E), butylated hydroxyl benzoic acids and their salts, peroxides, gallic acids and alkyl esters, sorbic acid, lipoic acid, amines, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, methionine, proline, superoxide dismutase, silymarin, tea extracts and mixtures thereof.

Examples of chelators include EDTA, NTA, hydoxamic acids, phytic acid, lactoferrin and those disclosed in US2014120131 or US2004132667 and mixtures thereof, A chelator means an agent capable of removing a metal ion by forming a complex so that the metal ion cannot participate in or catalyse chemical reactions. A chelator is useful for protection against UV radiation or other environmental agents that can cause skin damage.

It will be appreciated that a plurality of additional ingredients may be added. The amount of the additional ingredient may be from about 0.001 % to about 50% weight of the composition, preferably, about 0.01% to about 20%, preferably about 0.1% to about 10%, about 0.5% to about 10%, about 1% to about 5%, preferably 2% weight of the composition. The amount of additional ingredient included will depend on numerous factors, including the type of additional ingredient used, the nature of the additional ingredient, the components) of the topical composition, the amount of active or peptide in the topical composition and/or the intended use of the topical composition. The nature and amount of any additional ingredient should not unacceptably alter the benefits of the peptides of this invention. The topical composition may be alcohol free.

In some embodiments of the invention, the composition further comprises one or more additional active agents, in addition to the peptide of the invention (also known as the active of the composition). In addition, or alternatively, the compositio may be administered with one or more other additional active agents. Typical said additional active agent is present in trace amounts only. In some embodiments, there may be no additional active agent present in the composition. The amount of additional active agent included will depend on numerous factors, including the type of additional active agent used, the nature of the additional active agent, the component(s) of the topical composition, the amount of active or peptide in the topical composition and/or the intended use of the topical composition. The nature and amount of any additional active agent should not unacceptably alter the benefits of the peptides of this invention. It is to be understood that an ingredient that is considered to be an "active" ingredient in one product may be a "functional" or "excipient" ingredient in another and vice versa. It will also be appreciated that some ingredients play a dual role as both an active ingredient and as a functional or excipient ingredient. Examples of the additional active agents include glucose transport promoting drugs, skin supplement, agent for treatment and/or care of the skin, anti-inflammatory agent, an anti-aging agent, a cellular growth promoting agent and pharmacological enhancers. Such agents are well known in the art and it will be appreciated that any suitable additional active agent may be used. Additional active agents for treatment and/or care of the skin may include collagen synthesis agents, retinoids, exfoliating agents, anti-cellulite agents, elastase inhibiting agents, melanin synthesis stimulating or inhibiting agents, self-tanning agents, antiaging agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, and healing agents. Active agents also include anti-inflammatory agents.

Any additional active agent should be suitable for application to the skin without undue toxicity, incompatibility and/or allergic reaction.

It will be understood that the classificatio gi ven herein is for clarity and convenience only and not intended to limit the additional ingredient, excipient, or active to that particular application or category listed.

In a particularly preferred embodiment, the methods and uses of the invention involve administration of a peptide or composition of the invention in combination with one or more other active agents, for example, existing growth promoting drags or pharmacological enhancers available on the market. In such cases, the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.

The effect of the current invention is accomplished by topical application or administration of the topical composition of the invention described herein to a person, animal or a patient in need of treatment or care. Topical delivery preferably means delivery to a keratinous layer such as the skin, hair and/or nails, but can also mean delivery to a body lumen lined with epithelial cells, for example the lungs or airways, the gastrointestinal tract, the buccal cavity. The effect may be confined to the surface of the skin or may be within the skin or a combination of both. The topical composition of the invention is administered in a cosmetically or pharmaceutically effective amount. In other words, in an amount that is non-toxic but sufficient amount to provide the desired effect. It will be appreciated that a person skilled in the art would be capable of determining an appropriate dose of the topical compositions of the invention to administer without undue experimentation. Alternatively, a physician will determine the actual dose that is most suitable for a patient depending on the particular condition, disease or disorder to be treated or cared for and the age, body weight and/or health of the person. It will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. For example, the composition may be administered at a dose of from 0.01 to 50 mg/kg body weight, such as from 0.1 to 30 mg/kg, more preferably from 0.1 to 20 mg/kg body weight, more preferably from 0.1 to 10 mg/kg body weight, preferably 0.1 to 5 mg/kg body weight. In an exemplary embodiment, one or more doses of 10 to 300 mg/day or more preferably, 10 to 150 mg/day, will be administered to the patient. The amount and the frequency is as best suited to the purpose. The frequency of application or administration can vary greatly, depending on the needs of each subject, with a recommendation of an application or administration range from once a month to ten times a day, preferably from once a week to four times a day, more preferably from three times a week to three times a day, even more preferably once or twice a day.

In preferred embodiments, repeated use of the topical composition is provided.

The topical composition may be applied by, but not limited to, rubbing, or massaging into the keratinous tissue, skin or area of the body to be treated or cared for. In some embodiments, the composition is left on or not removed from the area of the body. In other embodiments, the composition is removed after a period of time, such as, but not limited to, from about 2 minutes to 60 minutes, from about 5 minutes to about 30 minutes, preferably from about 10 minutes to about 20 minutes, The composition may be removed immediately after application. In some embodiments of the current invention, the composition of the invention may be applied to an area to be treated by means to achieve a greater penetration of the composition and/or peptide of the invention, such as, but not limited to, iontophoresis, sonophoresis, elcctroporation, microelectric patches, mechanical pressure, osmotic pressure gradient, occlusive cure. microinjections or needle-free injections by means of pressure, such as injections by oxygen pressure, or any combination thereof.

The peptides of the invention are used in the topical cosmetic or pharmaceutical composition of this invention at cosmetically or pharmaceutically effective concentrations to achieve the desired effect; in a preferred form with regards to the total weight of the composition, between 0.00000001% (in weight) and 20% (in weight); preferably between 0.000001 % (in weight) and 15% (in weight), more preferably between 0.0001 % (in weight) and 10% (in weight) and even more preferably between 0.0001% (in weight) and 5% (in weight). Ideally, the peptides of the present invention are preferably used from about 0.00001 % w/w to about 0.5% w/w, and more preferably from 0.00005 w/w to about 0.05 w/w, and most preferably from about 0.0001 w/w to about 0.01 w/w of the composition. Ideally, the peptides of the present invention are preferably used from about 0.0001% w/w to about 0.004% w/w of the composition.

In some embodiments of the current invention, the composition may be delivered via any one of liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, millicapsules, capsules, macrocapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, surfactant-phospholipid mixed micelles, millispheres, spheres, lipospheres, particles, nanospheres, nanoparticles.milliparticles, solid nanopartciles as well as microemulsions including water-in-oil microemulsions with an internal structure of reverse micelle and nanoemulsions microspheres, microparticles. A variety of methods are available for preparing liposomes. See, e.g., Szoka et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980), U.S. Pat. Nos. 4,186,183 _» 4,217,344, 4,235,871 , 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, 4,235,871 , 4,261 ,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, 4,946,787, PCT Publication No. WO 91/17424, Deamcr & Bangham, Biochim. Biophys. Acta 443:629-634 (1976); Fraley, et al., PNAS 76:3348-3352 (1979); Hope et al., Biochim. Biophys. Acta 812:55-65 (1985); Mayer et al., Biochim. Biophys. Acta 858: 161-168 ( 1986); Williams et al., PNAS 85:242-246 (1988); Liposomes (Ostro (ed.), 1983, Chapter 1); Hope et al., Chem. Phys. Lip. 40:89 (1986); Gregoriadis, Liposome Technology (1984) and Lasic, Liposomes: from Physics to Applications (1993)). Suitable methods include, for example, sonication, extrusion, high prcssure/homogenization, microfluidization, detergent dialysis, calcium-induced fusion of small liposome vehicles and ether fusion methods, all of which are well known in the art. These delivery systems may be adapted to achieve a greater penetration of the compound and/or peptides of the invention. This may improve pharmacokinetic and pharmacodynamics properties. The delivery system may be a sustained release system wherein the compound or peptide of the invention is gradually released during a period of time and preferably with a constant release rate over a period of time. The delivery systems are prepared by methods known in the art. The amount of peptide contained in the sustained release system will depend on where the composition is to be delivered and the duration of the release as well as the type of the condition, disease and/or disorder to be treated or cared for.

The topical composition of the invention may be for human or animal usage in human and veterinary medicine.

The topical composition of the invention may be used for pharmaceutical, personal care and/or cosmetic uses.

The composition can be used to treat or care for any disease, disorder or condition of the skin, including but not limited to, psoriasis, dermatitis, allergic dermatitis, eczema, spongiosis, edema, skin cancer, ulcers, acne, scars, cellulitis, elastosis, keratosis, rosacea, varicose veins, inflammatory disorders.

The topical composition may be used to for treating or caring for visible signs of aging including but not limited to wrinkles, stretch marks and dark circles, dryness, fine lines, age spots, red blotches, sagging skin, and conditions caused by sun exposure including sunburn, stress, pollution and/diet. The topical composition may also be used for delaying, slowing or inhibiting the skins or the onset of aging. The composition may be administered by a medical device, such as a plaster or a patch as described herein.

The topical composition may be used to treat or care for a wound in a mammal. In another embodiment, the topical composition is for use in the treatment or prevention of a disease or condition characterised by damaged epithelial cells or tissue, and/or damaged dermal or epithelial cells or tissue. The disease may be but is not limited to cancer and trauma.

The topical composition may be used to treat or care for any muscle condition, to improve, muscle status in a mammal, to promote recovery of muscle, typically following exercise, to maintain or restore muscle health (for example lean tissue mass) in a mammal, to enhance physical performance, in treatment or prevention of a disease or condition characterised by lethargy or low energy levels. The topical composition may be used to promote growth of a tissue, promote growth of epithelial tissue, promote growth of skin, promote growth of an organ, promote growth of an organism. The skin can have a normal pathology and/or an abnormal pathology,

The topical composition may also be used to treat or care for any inflammatory disorder.

In one embodiment the inflammatory disorder is an inflammatory disorder of the joints. In one embodiment the inflammatory disorder is an inflammatory disorder of the cardiovascular system. In one embodiment the inflammatory disorder is an autoimmune disease. In one embodiment the inflammatory disorder is a lung and airway inflammatory disorder. In one embodiment the inflammatory disorder is an intestinal inflammatory disorder. In one embodiment the inflammatory disorder is dermatitis. In one embodiment the inflammatory disorder is acne vulgaris. In one embodiment the inflammatory disorder is psoriasis. In one embodiment the inflammatory disorder is rheumatoid arthritis. In one embodiment the inflammatory disorder is cardiovascular disease. In one embodiment the inflammatory disorder is atherosclerosis. In one embodiment the inflammatory disorder is Type I diabetes.

In one embodiment the inflammatory disorder is Graves disease. In one embodiment the inflammatory disorder is Guillain-Barre disease. In one embodiment the inflammatory disorder is Lupus. In one embodiment the inflammatory disorder is Psoriatic arthritis, In one embodiment the inflammatory disorder is Ulcerative colitis. In one embodiment the inflammatory disorder is asthma. In one embodiment the inflammatory disorder is cystic fibrosis. In one embodiment the inflammatory disorder is COPD. In one embodiment the inflammatory disorder is emphysema. In one embodiment the Inflammatory disorder Is acute respiratory distress syndrome. In one embodiment the inflammatory disorder is colitis. In one embodiment the inflammatory disorder is inflammatory bowel disease.

The topical composition may also be used to treat or care for a metabolic disorder.

In one embodiment, the metabolic disorder is pre-diabetes. In one embodiment, the metabolic disorder is diabetes. In one embodiment, the metabolic disorder is Typc- 1 diabetes. In one embodiment, the metabolic disorder is Type-2 diabetes. In one embodiment, the metabolic disorder is metabolic syndrome. In one embodiment, the metabolic disorder is obesity. In one embodiment, the metabolic disorder is diabetic dyslipidemia. In one embodiment, the metabolic disorder is hyperlipidemia. In one embodiment, the metabolic disorder is hypertension. In one embodiment, the metabolic disorder is hypertriglyceridemia. In one embodiment, the metabolic disorder is hyperfattyacidemia. In one embodiment, the metabolic disorder is hypercholerterolemia. In one embodiment, the metabolic disorder is hyperinsulinemia. In one embodiment, the metabolic disorder is MODY

In an embodiment of the invention the composition is for use in maintaining or restoring gut health.

In an embodiment of the invention the composition is for use in treatment or prevention of pain.

The topical composition has a used as a person care product, a supplement, a cosmetic, a pharmaceutical product.

A method of treating, preventing or caring for any one of the diseases, disorders or conditions described herein is also provided, said method comprising a step of administering the topical composition of the invention. The composition may be administered to the skin, hair, the nails. The composition may be administered in any dose or frequency as disclosed herein by any method of topical application.

In one embodiment the topical composition is a cosmetic composition. In one embodiment the topical composition is a pharmaceutical composition. It will be appreciated that the composition may have a dual function and be both a cosmetic and pharmaceutical composition.

It will be appreciated that the topical composition may be a therapeutic composition or may be a non-therapeutic composition. The topical composition may have a dual role.

In an embodiment of the invention the peptide may be a modified peptide. The term "modified peptide" is used interchangeably with the term derivative of the peptide. The modified peptide includes but is not limited to a peptide which has been substituted with one or more groups as defined herein.

In one embodiment, the modification may be any modification that provides the peptides and or the composition of the invention with an increased ability to penetrate a cell. In one embodiment, the modification may be any modification that increases the half-life of the composition or peptides of the invention. In one embodiment, the modification may be any modification that increases activity of the composition or peptides of the invention. In one embodiment, the modification may be any modification that increases selectivity of the composition or peptides of the invention.

In one embodiment, the group is a protecting group. The protecting group may be an N -terminal protecting group, a C-terminal protecting group or a side-chain protecting group. The peptide may have one or more of these protecting groups. The person skilled in the art is aware of suitable techniques to react amino acids with these protecting groups. These groups can be added by preparation methods known in the art, for example the methods as outlined in paragraphs [0104] to [0107] of US2014120141. The groups may remain on the peptide or may be removed, The protecting group may be added during synthesis.

In an embodiment of the invention the peptides may be substituted with a group selected from one or more straight chain or branched chain, long or short chain, saturated, or unsaturated, substituted with a hydroxyl, amino, amino acyl, sulfate or sulphide group or unsubstituted having from 1 to 29 carbon atoms, N-acyl derivatives include acyl groups derived from acetic acid, capric acid, lauric acid, myristic acid, octanoic acid, palmitic acid, stearic acid, behenic acid,, linoleic acid, linolenic acid, lipoic acid, oleic acid, isosteric acid, elaidoic acid, 2- ethylhexaneic acid, coconut oil fatty acid, tallow fatty acid, hardened tallow fatty acid, palm kernel fatty acid, lanolin fatty acid or similar acids. These may be substituted or unsubstituted. When substituted they are preferably substituted with hydroxyl, or sulphur containing groups such as but not limited to SO3H, SH, or S-S.

In an embodiment of the current invention, the peptide is Ri-X- R ₃ .

Ri and/or R ₂ groups respectively bound to the ami no-terminal (N-terminal) and carboxy!- terminal (C-tcrminal) of the peptide sequence.

In one embodiment, the peptide is Ri-X. Alternatively, the peptide is X- R2. Preferably, Rj is H, C alkyl, acetyl, benzoyl or trifluoroacetyl;

X is the peptide of the invention;

R ₂ is OH or NHa.

In an embodiment, R i is selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyc!yl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, Tert-butyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (Fmoc) and R5-CO-, wherein Rs is selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylalkyl; R?. is selected from the group formed by -NR3R4, -OR3 and -SR3, wherein R ₃ and R ₄ are independently selected from the group formed by H, a non-cyclic substituted or unsubstituted aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl; and with the condition that Ri and R ₂ are not a-amino acids.

In accordance with another preferred embodiment, R ₂ is -NR3R4, -OR ₃ or -SR ₃ wherein R ₃ and R4 are independently selected from the group formed by H, substituted or unsubstituted C i-C 24 alkyl, substituted or unsubstituted C2-C ₂ 4 alkcnyl, Tert-butyloxycarbonyl, 9- fluorenyhnethyloxycarbonyl (Fmoc), substituted or unsubstituted C2-C 2 alkynyl, substituted or unsubstituted C ₃ -C 24 cycloa!kyl. substituted or unsubstituted C s-C ₂ cycloalkenyl, substituted or unsubstituted Cg-C 21 cycloalkynyl. substituted or unsubstituted C {,-C 30 aryl, substituted or unsubstituted C7-C24 aralkyl, substituted or unsubstituted heterocyclyl ring of 3- 10 members, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than carbon wherein the alkyl chain is of 1 to 6 carbon atoms. Optionally, R 3 and R can be bound by a saturated or unsaturated carbon-carbon bond, forming a cycle with the nitrogen atom. More preferably R ₂ is -NR3R4 or -OR 3, wherein R3 and R4 are independently selected from the group formed by H, substituted or unsubstituted Ci-C 24 alkyl, substituted or unsubstituted C2-C24 alkenyl, substituted or unsubstituted C2-C24 alkynyl, substituted or unsubstituted C3-C10 eycloa!kyl, substituted or unsubstituted C -C 15 aryl and substituted or unsubstituted heterocyclyl of 3-10 members, substituted or unsubstituted heteroarylalkyl with a ring of 3 to 10 members and an alkyl chain of 1 to 6 carbon atoms. More preferably ¾ and R are selected from the group formed by H, methyl, ethyl, hexyl, dodecyl, or hexadecyl. Even more preferably Rj is H and R.» is selected from the group formed by H, methyl, ethyl, hexyl, dodecyl, or hexadecyl. In accordance with an even more preferred embodiment, R ₂ is selected from -OH and -NH ₂ .

In accordance with another embodiment of this invention I s is selected from the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl, and R ₂ is -NR3R 4 or -OR3 wherein R3 and R4 are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R2 is -OH or -NH ₂ More preferably, Ri is acetyl or palmitoyl and R2 is -NH ₂ .

In a preferred embodiment, the acyl group is bound to the N-terminal end of at least one amino acid of the peptide.

In an embodiment of the invention, the peptide is modified to comprise a side chain protecting group. The side chain protecting group may be one or more of the group comprising benzyl or benzyl based groups, t-butyl-based groups, benzyloxy-carbonyl (Z) group, and allyloxycarbonyl (alloc) protecting group. The side chain protecting group may be derived from an achiral amino acid such as achiral glycine. The use of an achiral amino acid helps to stabilise the resultant peptide and also facilitate the facile synthesis route of the present invention. Preferably, the peptide further comprises a modified C-temiinus, preferably an amidated C-terminus. The achiral residue may be alpha-aminoisobutyric acid (methylalaine). It will be appreciated that the specific side chain protecting groups used will depend on the sequence of the peptide and the type of N-terminal protecting group used.

In one embodiment of the invention the peptide is conjugated, linked or fused to one or more polyethylene glycol polymers or other compounds, such as molecular weight increasing compounds. The molecular weight increasing compound is any compound that will increase the molecular weight, typically by 10% to 90%, or 20% to 50% of the resulting conjugate and may have a molecular weight of between 200 and 20, 000, preferably between 500 and 10. 000. The molecular weight increasing compound may be PEG, any wate -so 1 ub le(amph iphi 1 ic or hydrophilic) polymer moiety, homo or co-polymers of PEG, a monomethyl-subsitututed polymer of PEG (mPEG) and polyoxyethylene glycerol (POG), polyamino acids such as poly- lysine, poly- glutamic acid, poly-asparti acid, particular those of L conformation, pharmacologically inactive proteins such as albumin, gelatin, a fatty acid, olysaccharide, a lipid amino acid and dextran. The polymer moiety may be straight chained or branched and it may have a molecular weight of 500 to 400QQDa, 5000 to 10000 Da, 10000 to 5000, Da. The compound may be any suitable cell penetrating compound, such as tat peptide, penetratin, pep- 1. The compound may be an antibody molecule. The compound may be a lipophilic moiety or a polymeric moiety.

The lipophilic substituent and polymeric substituents are known in the art. The lipophilic substituent includes an acyl group, a sulphonyl group, an N atom, an O atom or an S atom which forms part of the ester, sulphonyl ester, thioester, amide or sulphonamide. The lipophilic moiety may include a hydrocarbon chain having 4 to 30 C atoms, preferably between 8 and 12 C atoms. It may be linear or branched, saturated or unsaturated. The hydrocarbon chain may be further substituted. It may be cycloalkanc or heterocycloalkane.

The peptide may be modified at the N-terminal, C-terminal or both. The polymer or compound is preferably linked to an amino, carboxyl or thio group and may be linked by N -termini or C- termini of side chains of any amino acid residue. The polymer or compound may be conjugated to the side chain of any suitable residue.

The polymer or compound may be conjugated via a spacer. The spacer may be a natural or unnatural amino acid, succinic acid, lysyl, glutamyl, asparagyl, glycyl, beta-alanyl, gamma- amino butanoyl.

The polymer or compound may be conjugated via an ester, a sulphonyl ester, a thioester, an amide, a carbamate, a urea, a sulphonamide.

A person skilled in the art is aware of suitable means to prepare the described con jugate.

Compositions may be formulated in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.

In a particularly preferred embodiment, the methods and uses of the invention involve administration of a peptide or composition of the invention in combination with one or more other active agents available on the market. In such cases, the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents EXAMPLES

EXAMPLE 1 to 9; Formulations

In a preferred embodiment, the composition is formulated as a cosmetic as defined herein. In one embodiment the cosmetic is an emulsion or cream or a rub, such as a muscle rub.

In an embodiment the cream comprises an excipient or diluent, a suspending agent, a preservative and an amount of at least one peptide of the invention.

In an embodiment the cream comprises an alcohol, a carbomer, a sorbate, water and at least one peptide of the invention. Preferably the alcohol is butylene glycol (1,3-butanediol). The alcohol may be present in an amount of between 1 and 10 % of the composition, preferably between 2 and 6%, preferably 4%. The sorbate may be polysorbate-20. The sorbate may be present in an amount of between .01 to 1% of the composition, preferably between .05 and .5%, preferably 0, 10%. Water is present in an amount of between 10% and 90%, preferably 30% to 75%. The carbomer may be present in an amount of from 0.05% to 1 %, preferably, 0.1% to 0.5%, preferably, 0.15%. The carbomer may be Ultrez 10.

The peptide of the invention may be present in an amount of from 0.5% to 10%, preferably, 1% to 5%, preferably 3%.

The composition may further comprise one or more of sugar alcohol such as glycerine, parabens, silicon, such as cyclohcxasiloxane, a fatty alcohol or phosphoric acid or a mixture of fatty alcohol and phosphoric acid, such as cctearyl alcohol, dicetyl phosphate and Cereth 10 phosphate or combinations thereof, a polyoxyethylene stearyl ethers, such as Steareth 2 and 10, and a fragrance.

An exemplary rub or emulsion is follows in Example I.

The resulting emulsion is suited as a rub. In addition, the rub is suitable for fragile aged skin. The emulsion is suitable for improving fine lines, wrinkles, dryness reducing redness and irritation.

Percentages are examples only and it will be appreciated that any suitable percentage may be used depending on the use.

The emulsion is prepared in the following way; Phase A: disperse Ultrez 10 (carbomer) in water and let is swell for 20 minutes, then add phase B; heat to 75°C. Heat Phase C separately to 75°C. Mix the two phases under stirring, homogenise, add Phase D, neutralise with Phase E, cool until reaching 30°C ₅ then add Phase F and Phase G; adjust to pH to 6 with -NaOII. It will be understood that this is an example only and any suitable method known in the art may be used. In a further embodiment, the composition may comprise one or more of water, a carbomer, a sorbate such as potassium sorbate, a sugar alcohol, such as glycerine, an alcohol such as 2-(2- Ethoxyethoxy)ethanol, a polyoxyethylene stearyl ethers, such as Stcareth 2, a fatty alcohol or phosphoric acid or a mixture of fatty alcohol and phosphoric acid , such as cetearyl alcohol, dicetyl phosphate and Cereth 10 phosphate or combinations thereof, a siloxane, such as cyclomcthicone, a Caprylic Capric Triglycerides, a sorbitan Stearate, Parabens, Sodium hydroxide, an active agent such as a skin lightening agent, such as a mixture of lycerin (and) Butylene Glycol (and) Arcostaphylus Uva Ursi Leaf Extract (and) Mitracarpus Scaber Extract (ETIOLINE®), or a muscle health agent and peptide of the invention, The following composition in Example 2 is an example of an emulsion or cream or a rub.

The active can be ETIOLINE ( ) [Glycerine (and) Etylene Glycol (and)Arcostaphylus uva leaf extract and Mitracarpus Scaber extract] ETIOLINE ® is a skin lightening ingredient sold by SEDERMA (WO 98/05299 of Nov. 19, 1996).

It will be understood that ETIOLINE can be replaced with any active agent, such as an agent that aids muscle health, development or recovery.

This formulation can be made according to the procedures generally outlined in Example 1 . The composition may be an emulsion or cream or rub comprising one or more of water, a carbomer, such as Ultrez 10, a sugar alcohol, such as glycerine, an alcohol such as phenova (phenoxyethanol and mixed parabens), a fatty acid ester such as ethylhexyl palmitate, a fatty alcohol such as cetearyl alcohol, a lactic acid ester such as myristyl lactate, a sorbate such as polysorbate 20 and/or potassium sorbate, a polymeric emulsifier such as Acrylate (CIO -30 alkyl acrylate) and a cross polymer, a siloxane, such as cyclomethicone, sodium hydroxide, at least one active agent, such as a muscle health agent or an agent for the treatment of stretch marks, such as siegesbeckia Orientalis extract (Darutoside) and a peptide.

The following composition in Example 3 is an example of an emulsion or cream. In an embodiment, the emulsion or cream is an anti-stretch mark cream.

The active can be Daratoside (Siegesbeekia Orie talis Extract). Darutoside is a molecule sold by SEDERMA for the treatment of stretch marks. It will be understood Daratoside can be replaced with any active agent, such as any agent that aids muscle health, development or recovery.

This emulsion or rub is prepared in the following way: Phase A disperse Ultrez 10 (earbomer) in water and let it swell for 20 minutes, then add phase B; heat to 75°C. Heat Phase C separately to 75°C. Mix the two phases under stirring, homogenise, add Phase D, neutralise with Phase E, cool until reaching 30°C, then add Phase F and Phase G, adjust pH to -6 with NaOI I. In an embodiment of the invention the composition may be an emulsion, cream or a gel, preferably a gel, comprising one or more of water, a earbomer, such as Ultrez 10, a sugar alcohol, such as glycerine, an alcohol such as phenova (phenoxyethanol and mixed parabens), a sorbate such as polysorbate 20 and/or potassium sorbate, a polymeric emulsifier such as Acrylate (CIO -30 alkyl acrylate). a siioxane, such as cyclomethicone, sodium hydroxide, a peptide and at least one agent such as an agent for muscle health, recovery or development, or a suitable moisturising agent, such as an agent comprising lmpcrata Cylindrica (root) extract, water, glycerine, PEG-8, and earbomer (MOIST 24). In an embodiment, the gel is a moisturising gel.

The following composition in Example 4 is an example of a gel In an embodiment, the gel is a moisturising gel.

This formulation can be made according to the procedures generally outlined in Example 3 The active can be MOIST-24 (R) [Imperata Cylindrica (root) Extract (and) water (and) Glycerin (and) PEG- 8 (and) Carbomer] . It will be understood that any agent can be used to replace MOIST-24, For example, any agent that aids muscle health, development or recovery .

In an embodiment of the invention the composition may be art emulsion, cream or rub comprising one or more of water, a carbomer, such as Ultrez 10, a sorbate such as polysorbate 20, polysorbate 60 and/or potassium sorbate, an alcohol such as phenova (phenoxyethanol and mixed parabens), butylene glycol ( 1 ,3-butanediol), lanolin alcohol, and/or cetearyi alcohol, vsorbitan stearate, Poly dimethyl siloxane such as dimethicone, an isotridetyl isononanoate, a caprylic/capric triglyceride, a cetyl ester, sodium hydroxide, water, an agent for muscle health, recovery and/or development, or an anti-aging agent, such as an agent comprising butylene glycol, water, Iaureth-3, hydroxyethyl cellulose and acetyl-dipeptide- l-cetylestcr

(CALMOSENSINE®).

The following composition in Example 5 is an example of a cream or a rub.

This formulation can be made according to the procedures generally outlined in Example 3. The active can be CALMOSENSINE (R) [Butyiene Glycol (and) water (and) Laureth-3 (and)Hydroxyethylcellulose (and) Acetyl-Dipcptidc- 1 -cetylester] Calmoscnsine(R) is an analgesic peptide offered by SEDERMA (WO 98/07744 of Feb. 26, 1998). It will be understood that any agent can be used to replace CALMOSENSINE, For example, any agent that aids muscle health, development or recovery.

In an embodiment of the invention the composition may be an emulsion, cream or rub comprising one or more of water, a carbomer, such as Ultrez 10, a sugar alcohol, such as glycerine, a sorbate such as potassium sorbate, a steareth such as Steareth 10, a fatty alcohol or phosphoric acid or a mixture of fatty alcohol and phosphoric acid , such as cetearyl alcohol, dicetyl phosphate and Cereth 10 phosphate or combinations thereof, diethyhexyi succinate, mixed parabens, Sorbitan Stearate, Sodium Hydroxide, water, a peptide, and an acti ve agent, such as an agent for muscle health, recovery and/or development or an agent for mature skin, such as one comprising Trifolium Pratense(Clover) Flower Extract (and) Glycerin (and) Butylene Glycol (and) Lecithin (TEROCARE®).

The following composition in Exam le 6 is an example of a cream or a rub.

This formulation can be made according to the procedures generally outlined in Example 3. The active agent can be STEROCARE (TM) [Trifoliiim Pratense (Clover) Flower Extract (and) Glycerin (and) Butylene Glycol (and) Lecithin Sterocare(R) is offered by SEDERMA as an active ingredient for mature skin (FR 2769502 of Apr, 14, 2000, WO 99/18927 of Apr. 22, 1999). It will be understood that any agent can be used to replace STEROCARE®. For example, any agent that aids muscle health, development or recovery.

The following composition in Example 7 is an example of a rub or a tonic.

The following composition in Example 8 is an example of a cream or a rub.

The agent can be Deferoxamine and/or Berberine, These are used as skin thickeners. Deferoxamine and Berberine can be replaced with another active agents, such as an agent for muscle health, recovery and development.

The following composition in Example 9 is an example of a gel or rub.

This gel can be prepared in the following way: Homogenize Part B and pour it into Part A. Heat Part (A+B) to 75°C. Heat Part C and Part D to 75°C. Pour Part C into Part (A+B) with helix stirring; then, pour Part D into Part (A+B+C). Add Part F and Part E. Pour Part G at about 35°C.

The active can be Rutin and or Bowman Birk Inhibitor, These agents are used for tissue regeneration. Rutin and Bowman Birk Inhibitor can be replaced with another active agent, such as an agent for muscle health, recovery and development. Example 10

Glucose transport activity Study Description

Skeletal muscle is the predominant site of glucose disposal (80%) under insulin-stimulated or post-prandial conditions. Under these conditions, transport of glucose into skeletal muscle is facilitated principally by the insulin-responsive glucose transport protein GLUT4, which translocates to the cell surface upon insulin or contractile stimulation.

The effect of six synthetic peptides (SP1-6) on in vitro GLUT4 translocation using the L6 rat skeletal muscle cell line was determined. A clone of the L6 cell line containing ovcrcxprcssion of GLUT4 tagged with a c-myc epitope (courtesy of Prof. Amira Klip, Hospital for Sick Children, Toronto) was used to investigate the efficacy of each SP and protein composition! for effects on GLUT4 translocation in a dose-response design. SP2 [SEQ ID 1] is a peptide of the invention, whereas peptides SP 1 and SP3-SP6 are comparative peptides.

SP1 (E_685two_BE) DTFYNAAWDPSNR [SEQ ID 1 15]

SP2 (E_64two_BE) VLDLAIPVNRPGQL [SEQ ID 1]

SP3 (E_93_DE) YQHQQGGKQEQENEGNNIFSGPK [SEQ ID 1 16]

SP4 (I_641 JBE) ALD AI ANLLR [SEQ ID 1 17]

SP5 (IJ 021 JBE) YDYENVDAGAA [SEQ ID 1 18]

SP6 (I_24_BE) EVQDSPLDACR [SEQ ID 1 19]

Methodology

Cell culture

L6-GLUT4myc cells were grown in 10% FBS and 2 pg/ ^' ml blasticidin. Cells were grown for 48-72 hours before being seeded in 24-well plates at 15,000 cells per well in 2% FBS and allowed to differentiate for 6 to 8 days prior to experimentation. Experimental design

L6-GLUT4myc cells were seram-starved for three hours prior to incubation with 100 nM of insulin for 30mins, or 200, 20, 2,0 and 0.2 μΜ of SP, and 2, 1 , 0.5 and .25mg/ml of composition for 3 hours respectively. A 3 hour incubation period was selected based on previous findings identifying that incubation with branch chain amino acid containing di-peptides for 3 hours increases glucose uptake in L6 myotubes 1. Treatments were staggered in order to determine GLUT4myc translocation at the same time point.

Measurement of GLUT4myc translocation in L6 myotubes

The quantity of myc-tagged GLU ^' 1 ^' 4 at the cell surface was measured by antibody-coupled colorimetric assay. Briefly, after incubation with either insulin for 30mins or synthetic peptide or protein composition for 3 hours respectively, L6-GLUT4myc cells were fixed via incubation with 3% paraformaldehyde (PFA). A 01 M glycine solution was then added to quench PFA and cells were blocked with 5% goat serum. The myotube monolayer was exposed to anti-myc antibody and then incubated with peroxidase conjugated donkey anti-mouse IgG. 1 ml... of o- phenylenediamine dihydrochloride (OPD) reagent was added to each well and this reaction was stopped by adding 250μ1½ε11 of 3 M HCL. To determine GLUT4 translocation to cell surface, a measured aliquot of each condition was determined spectrophotometrically on a plate reader using absorbance at 492nm.

Synthetic peptides

Peptides were first diluted in a suitable solvent. Dimethyl sulfoxide (DMSO) was the solvent of choice for peptides with poor predicted water solubility. Final concentration of DMSO in each well at 200, 20, 2 and .2 μΜ for each synthetic peptide are shown in Table 2

Table 1. Concentration of DMSO per well for each synthetic peptide

; Concentration of DMSO per well (%)

Peptide 200 μΜ 20 μΜ 2 μΜ 0.2 μ

SP1 (E_685two_BE) 4.0 0.4 0.04 0.004

SP2 (E_64twe_BE) 0.9 _¾ 0.09 ^; 0.009 : 0.000

SP3 (E_93_BE) . ^' 0.8 0.08 ί 0.008 0.0008

SP4 (1_641_BE) 0.2 0.02 0.002 0.0002

SP5 (I_1021_BE) 3.0 0.3 0.03 1 0.003

SP6 (I_24_BE) I 0.0 0.0 0.0 0.0

Results

Synthetic peptides

In addition to an untreated control, 100 nM insulin was utilised to stimulate a maximal GLUT4 translocation response i.e. a positive control in each experiment. The average increase in cell surface GLUT4 translocation in response to 100 nM insulin was 1.72-fold when compared to untreated control (Figure 1 ). Treatments were staggered so that alt conditions (untreated, insulin and sample) were processed at the same time-point. There was a trend for SP2 to increase GLUT4 translocation at a concentration ranging from 0.2 - 2 μΜ. SP1 at 200 uM tended to decrease translocation due to poor cell viability.

Conclusion of the experiment

SP2 displayed a trend for stimulatory effect on skeletal muscle GLUT4 translocation and its ability to facilitate glucose transport in skeletal muscle. EXAMPLE 11

Glucose uptake assay in vitro model: Hs Mc - Human skeletal muscle cells (Sigma - 150-Q5a)

Glucose detection assay: PrismColor Glucose Uptake Assay Kit (Molecutools, Dublin 15)

Principle

Measuring glucose uptake using 2-deoxyglucose (2-DG) is a widely accepted method used to investigate glucose uptake in skeletal muscle cells. 2-DG is taken up by glucose transporters and metabolized to 2-DG-6-phosphate (2-DG6P). The amount of accumulated non- metabolized 2-DG6P is proportional to glucose uptake by cells.

Method

1. Human skeletal myoblasts were seeded in a 96 well plate at 10,000 cells per well in Skeletal Muscle Differentiation medium and allowed to differentiated for 72h prior to experimentation.

2. The differentiated cells were serum starved for 24h prior to stimulation with insulin or synthetic peptides. After starvation, the serum free media was removed, cells rinsed with Phosphate Buffered Saline (PBS) and media replaced with 100 μΐ of Krebs- Ringer-Phosphate-HEPES (KRPH) and incubated for I h.

3. The cells were then stimulated with ΙΟΟηΜ insulin for 30 minutes or 5 μg ml, 0.5 Mg/ml or Ο.05μ§Λη1 synthetic peptide for 31i respectively.

4. Following stimulation the cells were incubated with 10 μΐ/well of 2-DG solution for 40 min and glucose uptake was measured using the 'PrismColor Glucose Uptake Assay Kit' (Molecutools), all steps were carried out according to the manufacturer's instructions.

5. Results were calculated as a percentage of the untreated control. An increase in

optical density reading indicates greater incorporation of 2-DG6P and increase in glucose uptake. Results

Treatment with SEQ ID NO.1 results in a significant increase in glucose uptake as illustrated by Figure 2. These results demonstrate the efficacy of SEQ No 1 to facilitate glucose transport in skeletal muscle.

The invention is not limited to the embodiments hereinbefore described which may be varied in construction and detail without departing from the spiri t of the invention,

SEQUENCES

PEPTIDE : LQGQNDQRGEIIR [SEQ ID 120]

PEPTIDE ; PNVNPWHNPRQGGF {SEQ ID 121]

PEPTIDE ; FYNEGDAPWALY [SEQ ID 122]

PEPTIDE ; FYNEGDAPW [SEQ ID 123]

PEPTIDE : FYNEGDAPW AL [SEQ ID 124]

PEPTIDE : FYNEGDAPWA [SEQ ID 125]

PEPTIDE : TNANS VSHLAGK [SEQ ID 125]

PEPTIDE : AMPVDVIANAYR [SEQ ID 127]

PEPTIDE : NWENVLLGLGVAGSAPGIEGDEIAPLAK [SEQ ID 128]

PEPTIDE : NVLLGLGVAGSAPGIEGDE [SEQ ID 129]

PEPTIDE : NWENVLLGLGVAGSAPGIEGDEIAPLAK [SEQ ID 1301

PEPTIDE : FNAPLAHLIMAGADVLAVPSR [SEQ ID 131]

PEPTIDE i FNAPLAHLIM [SEQ ID 132]

PEPTIDE : FNAPLAHLIMAGADVLAVPSR (SEQ ID 133]

PEPTIDE : WGTPAYEE VR [SEQ ID 134]

PEPTIDE : TGGLGDVLGGLPPAMAANGHR [SEQ ID 135]

PEPTIDE : YDQYKDAWDTSVVAEI [SEQ ID 136]

PEPTIDE : DAWDTSVVAEIK [SEQ ID 137]

PEPTIDE : VMViSPR [SEQ ID 138]

PEPTIDE : LTGITGIVNGMDVSEWDPSKDK [SEQ ID 139]

PEPTIDE : VLTVSPYYAEELISGIAR [SEQ ID 140]

PEPTIDE : EALQAEAGLPVDRK [SEQ ID 141]

PEPTIDE ; YDATTAIEAK [SEQ ID 142]

PEPTIDE : IPLIAFIGR [SEQ ID 143]

PEPTIDE : AGILEADR [SEQ ID 144]

PEPTIDE : IPLIAFIGR [SEQ ID 145]

PEPTIDE : VFIDHPSFLEK [SEQ ID 146]

PEPTIDE : GPDTGVDYKDNQM {SEQ ID 147]

PEPTIDE : IYGPDTGVDYKDNQMR [SEQ ID 148]

PEPTI DE : IYGPDTGVDYK [SEQ ID 149]

PEPTIDE : II NLNNNPYFK [SEQ ID 150]

PEPTIDE : APTGTFIASGVVVGKD (SEQ ID 151]

PEPTIDE : QNYLSGFSKNILE [SEQ ID 152]

PEPTIDE : TIKLPAGTIAYLVNRDDNEE (SEQ ID 153]

PEPTIDE : LAIPVNRPGQLQSFL [SEQ ID 154]

PEPTIDE : AIPVNRPGQLQ [SEQ ID 155]

PEPTIDE : PAGHPVAVK [SEQ ID 156]

PEPTIDE : VQNYKAKLSSGDVFVIPAG [SEQ ID 157)

PEPTIDE : NNQRNFLAGDEDNVISQIQRPVKE (SEQ ID 158]

PEPTIDE : INKQVQNYKAKLSSGDVFVIPAG [SEQ ID 159]

PEPTIDE : LAIPVNRPGQ [SEQ I D 160]

PEPTIDE : NFLAGDEDNVISQIQRPVKE [SEQ ID 161]

PEPTIDE : D L A I PVN R P GQLQS F [SEQ ID 162]

PEPTIDE : VI AGHPVAVK [SEQ ID 163]

PEPTIDE : DTIKLPAGTIAYLVNRDDNEE [SEQ ID 164]

PEPTIDE : LAIPVNRPGQLQSF [SEQ ID 165]

PEPTIDE : KQVQNYKAKLSSGDVFVIPAG [SEQ ID 166]

PEPTIDE : RGDTIKLPAGTIAYLVNRDDNEE [SEQ ID 167]

PEPTIDE : FLAGDEDNV1SQIQRPVKE [SEQ ID 168]

PEPTIDE : LAIPVNRPGQLQS [SEQ ID 169]

PEPTIDE : VLDLAIPVNRPGQLQ [SEQ ID 170]

PEPTIDE : DLAIPVNRPGQLQ [SEQ ID 171)

PEPTIDE : VFVIPAGHPVAVK (SEQ ID 172]

PEPTIDE : TIFLPQHTDADYILVVLSGK [SEQ ID 173] PEPTIDE ; NQRNFLAGDEDNVJSQIQRPVKE [SEQ ID 174]

PEPTIDE : LAIPVNRPGQLQ [SEQ ID 175]

PEPTIDE : HPVAVKASSNLDLLGFG [SEQ ID 176]

PEPTIDE : LAIPVNRPGQL [SEQ ID 177]

PEPTIDE : D LAIPVNRPGQL [SEQ ID 178]

PEPTIDE : SKPHTIFLPQHTDADYILWLSGK [SEQ ID 179]

PEPTIDE ; FVIPAGHPVAVK [SEQ ID 180]

PEPTIDE ; DLAIPV PGQLQS [SEQ ID 181]

PEPTIDE : SGDVFVI PAGHPVAVKASS LD [SEQ ID 182]

PEPTIDE : AIPVNRPGQLQSF [SEQ ID 183]

PEPTIDE : ELAFPGSAQEVDR [SEQ ID 184]

PEPTIDE : LAIPVNRPGQLQSFLLSG [SEQ ID 185]

PEPTIDE : VFVIPAGHPVAVKASSNLDLLGFG [SEQ ID 186]

PEPTIDE : AGHPVAVK [SEQ ID 187]

PEPTIDE ; HPVAVKASSIMLDLLGFGINAE (SEQ ID 188]

PEPTIDE : LAIPVNRPGQLQSFLLSGNQNQ (SEQ ID 189]

PEPTIDE : SGDVFVIPAG [SEQ ID 190]

PEPTIDE : GSLLLPHYNSRAIVIVTVNE [SEQ ID 191]

PEPTIDE : NFLAGDEDNVISQIQRPVK [SEQ ID 192]

PEPTIDE : SGDVFVIPAGHPVA [SEQ ID 193)

PEPTIDE : GSLLLPHYNSRAIVIV (SEQ ID 194]

PEPTIDE : RGDTIKIPAGTIAYLVNRDD [SEQ ID 19S]

PEPTIDE : SGDVFVIPAGHPVAVK [SEQ ID 196]

PEPTIDE : LSSGDVFVIPAGHPVAVK [SEQ ID 197]

PEPTIDE : LDLAIPVNRPGQL [SEQ ID 198]

PEPTIDE : AIPVNRPGQL [SEQ I D 199]

PEPTIDE : LAIPVNRPGQLQSFLL [SEQ ID 200]

PEPTI DE : PHTIFLPQHTDADYILVVLSGK [SEQ ID 201]

PEPTIDE : VFVIPAGHPVAV ASSNLD [SEQ ID 202]

PEPTIDE : LAIPVNRPGQLQSFL1.S [SEQ ID 203]

PEPTIDE : VLDLA!PVNRPGQLQSF [SEQ ID 204)

PEPTIDE : AIPVNRPGQLQS [SEQ ID 205]

PEPTIDE : DTIKLPAGTIAYLVNRDDNE [SEQ ID 206]

PEPTIDE : NY AKLSSGDVFVIPAG (SEQ ID 207]

PEPTIDE : GKAILTVLKPDDRNSFNLE [SEQ ID 208]

PEPTIDE : YKSKPHTIFLPQHTDAD[SEQ ID 209]

PEPTIDE : ASSNLDLLGFG[SEQ ID 210]

PEPTIDE : OEEEEQGEEEINK[SEQ ID 211]

PEPTIDE : YKSKPHT'FLPQHTD[SEQ ID 212]

PEPTIDE : VLDLAIPVNR[SEQ ID 213]

PEPTIDE ; FFEITPEKNPQLQDt.DIFVNSVEI [SEQ ID 214]

PEPTIDE : TIFLPQHTDADYIL[SEQ ID 215]

PEPTIDE : SFLLSGNQNQQNYLSG(SEQ ID 216]

PEPTIDE : SFLLSGNQNQQNYLSGFS(SEQ ID 217]

PEPTIDE : NQQEQRKEDDEEEEQGEEE[SEQ ID 218]

PEPTIDE : EEQGEEEINK[SEQ ID 219]

PEPTIDE : SRGPIYSNE[SEQ ID 220]

PEPTIDE : EDDEEEEQGEEEIN [SEQ ID 221]

PEPTIDE : DDEEEEQGEEEINK[SEQ ID 222]

PEPTIDE : KEDDEEEEQGEEEIN[SEQ ID 223]

PEPTIDE : KEDDEEEEQGEEJSEQ ID 224]

PEPTIDE : QR EDDEEEEQGEEE[SEQ ID 225]

PEPTIDE : KEDDEEEEQGEEEIN (SEQ ID 226]

PEPTIDE : KFDDEEEEQGEEE[SEQ ID 227]

PEPTIDE : HPVAITASSNLNLLG[SEQ ID 228]

PEPTIDE : ASSNLNLLGFGfSEQ ID 229]

PEPTIDE : !TASSNLNLLGFG[SEQ ID 230] PEPTIDE : ITASSNLNLLGFGINAE[SEQ ID 231]

PEPTIDE : S5NLNLLGFG[SEQ ID 232]

PEPTIDE : VDIVIPVNGPGKF[SEQ ID 233]

PEPTIDE : LVIPVNGPG FE[SEQ 10 234]

PEPTIDE : LVIPVNGPGKFEA[SEQ ID 235]

PEPTIDE : LRLVDLV1PVNGPG FE[SEQ ID 236]

PEPTIDE : YRAKPHTIFLPQHIDAD[SEQ ID 237]

PEPTIDE : HPVAH ASSNLNLLGFGINAE(SEQ ID 238]

PEPTIDE : SNLNLLGf GfSEQ ID 239]

PEPTIDE : HPVAITASSNLNLLGFGINAENNE[SEQ ID 240]

PEPTIDE : LVDLV!PVNGPGKFE[SEQ ID 241]

PEPTIDE : LVIPVNGPG F[SEQ ID 242]

PEPTIDE ; TIKLPAGTTSYIVNQDDE[SEQ ID 243]

PEPTIDE ; DLRLVDLVIPV GPGKFE[SEQ ID 244]

PEPTIDE : EDLRLVDLVIPVNGPGKF£[SEQ ID 245]

PEPTIDE : HPVA1TA5SNLNLLGFG[SEQ ID 246]

PEPTIDE ; LVDLVIPVNGPGKFEAFDLA fSEQ ID 247]

PEPTIDE : DNVISQIENPV EiSEQ ID 248]

PEPTIDE : WIIPAGHPVAITASSNLNLLGFG[SEQ ID 249]

PEPTIDE : LVDLVIPVNGPGKFEAF[SEQ ID 250]

PEPTIDE : YPQLQDLDL[SEQ ID 251]

PEPTIDE : VIPVNGPGKF(SEQ ID 252]

PEPTIDE ; SKKSLPSE[SEQ ID 253]

PEPTIDE : LPQHIDADLILWLSGKfSEQ ID 254]

PEPTIDE : RGDTIKLPAGTTSYLVNQD(SEQ ID 255]

PEPTIDE : IPVNGPGKF(SEQ ID 256]

PEPTIDE : LPQHIDADLfSEQ ID 257]

PEPTIDE : LVIPVNGPGK[SEQ ID 258]

PEPTIDE : IFLPQHIDAD(5EQ ID 259]

PEPTIDE : LPQHIDADJSEQ ID 260)

PEPTI DE : VIPVNGPGK[SEQ ID 261]

PEPTIDE : IFLPQHIDA[SEQ ID 262]

PEPTIDE : TIKLPAGTTSYLVNQDDEE[SEQ ID 263]

PEPTIDE : HGEWRPSYEKEEDEEEGQRER(SEQ ID 264]

PEPTIDE ; E RHGEWRPSYE EEDEEEGQRE[SEQ ID 265]

PEPTIDE : LPAGTTSYLVNQDDEEDLR(SEQ ID 266]

PEPTIDE ; PSYEKEEDEEE6QRER[SEQ ID 267]

PEPTIDE ; EKRHGEWRPSYE[$EQ ID 268]

PEPTIDE : TiKLPAGTTSYLVNQDDEED[SEQ ID 269)

PEPTIDE : HGEWRPSYE QEDEEE [SEQ ID270]

PEPTIDE : EWRPSYE EEDEEE[SEQ ID 271]

PEPTIDE : PSYEKEEDEEEGQR(SEQ ID 272]

PEPTIDE : EKEEDEEEGQR[SEQ ID 273)

PEPTIDE : EWRPSYEKEFDEEEGQRE[SEQ ID 274]

PEPTIDE : KEEDEEEGQRfSEQ ID 275]

PEPTIDE : VQPGRERWEREEDEEQVDE[SEQ ID 276]

PEPTIDE : DWIIPAGHPVAiSEQ ID 277]

PEPTIDE : HGEWRPSYEKQEDE[SEQ ID 278]

PEPTIDE : EEDEEEGQR[SEQ ID 279]

PEPTIDE : HGEWRPSYEKEEDEEEGQR[SEQ ID 280]

PEPTIDE : EEWRGSQRREDPEE[SEQ. ID 281]

PEPTIDE : REEDEEQVDEEWRGSQRREDPEE[SEQ ID 282]

PEPTIDE : RHGEWRPSY(5EQ ID 283]

PEPTIDE : HGEWRPSYEKQEDEE[SEQ ID 284]

PEPTIDE : VVIIPAGHPVAtSEQ ID 285]

PEPTIDE : HGE RPSYE[SEQ ID 286)

PEPTIDE : KEEDEEEGQRER[SEQ ID 287] PEPTIDE : WIIPAGHPVAIT(SEQ ID 288]

PEPTIDE : EKRHGEWRPSYEKEEDE[SEQ ID 289]

PEPTIDE : QVDEEWRGSQRREDPEE[SEQ ID 290]

PEPTIDE : GDTIKLPAGTTSYLVNQDDEEOLR[SEQ ID 291]

PEPTIDE : GSEPRVPAQRE[SEQ ID 292]

PEPTIDE : EEKRHGEWRPSYEKE[SEQ ID 293]

PEPTIDE : EWRPSYE EEDEEfSEQ ID 294]

PEPTIDE : NYDEGSEPRVPAQRE[SEQ ID 295]

PEPTIDE : VIIPAGHPVAIT[SEQ ID 296]

PEPTIDE : RHGEWRPSYE [SEQ ID 297]

PEPTIDE : NYDEGSEPR[SEQ ID 298]

PEPTIDE : WRPSYEKEEDEE[SEQ ID 299]

PEPTIDE : WRPSYEKQEDEEE[SEQ ID 300]

PEPTIDE : EKRHGEWRPSYE QEDEEEfSEQ ID 301]

PEPTIDE : VVII AGHPVAITA[SEQ ID 302]

PEPTIDE : RHGEWRPSYE[SEQ. ID 303J

PEPTIDE : GSDDNVISQIENPVKE[SEQ ID 304]

PEPTIDE : WIIPAGHPV[SEQ ID 305]

PEPTIDE : HGEWRPSY[SEQ ID 306]

PEPTIDE : RPSYEKEEDEEEGQR[SEQ ID 307]

PEPTIDE : HGEWRPSYEK[SEQ ID 308]

PEPTIDE : KRHGEWRPSYEKEEfSEQ ID 309]

PEPTIDE : WIIPAGHPVAITAS[SEQ ID 310]

PEPTIDE : RGDTI LPAGTTSYLV QDDEEDfSEQ ID 311]

PEPTIDE : KRHGEWRPSYEKQEDEEE(SEQ ID 312]

PEPTIDE : DEEQVDEEWRGSQRREDPEEISEQ ID 313]

PEPTIDE : RHGEWRPSYE(SEQ ID 314]

PEPTIDE : HGEWRPSYEKE[SEQ ID 315]

PEPTIDE : KRHGEWRPSYEKEEDEEE[SEQ ID 316}

PEPTIDE : E RHGEWRPSYEKEEDEEE[SEQ ID 317)

PEPTIDE : TI LPAGTTSYLVNQDDEEDLRLVD[SEQ ID 318]

PEPTIDE : WRPSYEKEEDEEEGQRE[SEQ ID 319]

PEPTIDE : KRHGEWRPSYEKEEDEE[SEQ ID 320]

PEPTIDE : WII AGHPVAI[SEQ ID 321]

PEPTIDE : EWRGSQRREDPEE[SEQ ID 322]

PEPTIDE : HGEWRPSYEKQEDEEEKQKJSEQ ID 323]

PEPTIDE : SGSDDNVISQIENPVKEfSEQ ID 324]

PEPTIDE : RPSYE EEDEEEGQRER[SEQ ID 325]

PEPTIDE : EKEEDEEEGQRER[SEQ ID 326]

PEPTIDE : HGEWRPSYEKQ[SEQ ID 327]

PEPTIDE : WRPSYE EEDEEE1SEQ ID 328]

PEPTIDE : LAKNKNQYLRGFS[SEQ ID 329)

PEPTIDE : NKNQYLRGFSjSEQ ID 330]

PEPTIDE : LRGFS NILE[SEQ ID 331]

PEPTIDE : LAKN NQYLRGFS N[SEQ ID 332]

PEPTIDE : TVLSPNDRNSY[SEQ ID 3331

PEPTIDE : QYLRGFS NILE[SEQ ID 334]

PEPTIDE : G AILTVLSPNDRN5YNLE(SEQ ID 335]

PEPTIDE : RGFSKNILEfSEQ. ID 336]

PEPTIDE : NKNQYLRGFSKN!LE[SEQ ID 337]

PEPTIDE : ASSNLNLLGFGI AE[SEQ ID 338]

PEPTIDE : ASSNLNLLGF[SEQ ID 339]

PEPTIDE : LAKNKNQYIRGFSK[SEQ ID 340]

PEPTIDE : RGDTIKLPAGTTSYl VNQDDEE(SEQ ID 341]

PEPTIDE : ARLSPGDVVIIPAGHPVAITASSN[SEQ ID 342]

PEPTIDE : VQRYEARLSPGD[5EQ ID 343]

PEPTIDE : ARLSPGDVVIIPAGHPVAIT[SEQ ID 344] PEPTIDE : RGDTIKLPAGTTSYLVNQDDEfSEQ ID 345]

PEPTIDE : A LSPGDVVIIPAGHPVA[SEQ ID 346]

PEPTIDE : GAL LPHYNSRAIWLLVNE(SEQ ID 347]

PEPTIDE : ARLSPGDVVIIPAGHPVAiTASS[SEQ ID 348]

PEPTIDE : LSP6 DVV1 IP AGHPVAITASSN LN LLGFG1 NA E N N ER [S EQ ID 349]

PEPTIDE : ARLSPGDWIIPAGHPVAITAS(SEQ ID 350]

PEPTIDE : LSPGDVVIIPAGHPVAITASSNL[SEQ ID 351]

PEPTIDE : ARLSPGDVVIIPAGHPVAITA[5EQ ID 352]

PEPTIDE : HGPVE PYTLLYPSSK[SEQ ID 353]

PEPTIDE : LDALEPDNRfSEQ ID 354]

PEPTIDE : OALEPDNRfSEQ ID 355]

PEPTIDE : HGSLHKNAMFVPHYNLNANSIIYAfSEQ ID 356]

PEPTIDE : LAGTSSV!NNLPLDVVAATFpEQ ID 357]

PEPTIDE I FREGDIIAVPTGIVFW[SEQ ID 358]

PEPTIDE : GTSSVINNLPLDWAATFNLQP.NE[SEQ ID 359]

PEPTIDE : KGAIVKVKGGLSIISPPE[SEQ ID 360]

PEPTIDE : RLAGTSSVINNLPLD[SEQ ID 361]

PEPTIDE ; AGTSSVINNLPLDVVAATFNLQRNE[SEQ ID 362]

PEPTIDE ; AGTSSVINNLPL[SEQ ID 363]

PEPTIDE : LAGTSSVINNLPLDWA[SEQ ID 364]

PEPTIDE : AGTSSVINNLPLDV[SEQ ID 365]

PEPTIDE I AGRIKTVTSLDLPVLRW[SEQ. ID 366]

PEPTIDE ; AGRIKTVTSLDLPVLR[SEQ ID 367]

PEPTIDE : FREGD1IAVPTGIVF[SEQ ID 368]

PEPTIDE ; AGTSSVINNLPLD[SEQ ID 369)

PEPTIDE : L AGTSS I N L P L [SE Q ID 370]

PEPTIDE : LAGTSSVINNLPLDW[SEQ ID 371]

PEPTIDE ; EGDIIAVPTGIVF[SEQ ID 372]

PEPTIDE : LAGTSSVt N N LP LD V[ S E Q ID 373]

PEPTIDE : AGRALTVPQNYAVAAK5LSD[SEQ ID 374]

PEPTIDE : AGRALTVPQNYA[SEQ ID 375]

PEPTIDE : LAGTSSVINNLPLDISEQ ID 376]

PEPTIDE : RAGIARLAGTSSVINNLPLDVVA[SEQ ID 377]

PEPTIDE ; RASSNLNLLGFG!NAEJSEQ ID 378]

PEPTIDE : VTVNEG GDFEL[SEQ ID 379]

PEPTIDE : VRASSNLNLLGFGINAE[SEQ ID 380]

PEPTIDE : VRASSNLNLLGFGfSEQ ID 331]

PEPTIDE : H PVAVRASSNL LLG FG [SE Q ID 382]

PEPTIDE : TKNQVQSYKAKLTPGD[SEQ ID 383)

PEPTIDE : H PVAVRASSNLN LLG[SEQ ID 384]

PEPTIDE : KAKLTPGDVFVIPAG[SEQ ID 385]

PEPTIDE : DLTFPGSAQEVDRLLENQKfSEQ ID 386]

PEPTIDE ; PAGHPVAVRfSEQ ID 387]

PEPTI DE : A LTPGDVFVIPAGHPVA(SEQ ID 388]

PEPTIDE ; SYKAKLTPGDVFVIPAGHPVA[SEQ ID 389]

PEPTIDE : LTPGDVFVIPAGHPVAVR[SEQ ID 390]

PEPTIDE : VQSYKAKLTPGDVFVIPAG[SEQ ID 391]

PEPTIDE ; YKA LTPGDVFVIPAGHPVA[SEQ ID 392J

PEPTIDE : FVIPAGHPVAVR|SEQ ID 393]

PEPTIDE : YKAKLTPGDVFVIPAG[SEQ ID 394]

PEPTIDE : DLTFPGSAQEVDR[SEQ ID 395)

PEPTIDE : AKLTPGDVFVIPAGHPVAVR[SEQ ID 396]

PEPTIDE : LTPGDVFVIPAG[SEQ ID 397]

PEPTIDE : SYKAKLTPGDVFVIPAG[SEQ ID 398]

PEPTIDE : SYKAKLTPGDVFVIPAGHPVAVR[SEQ ID 399]

PEPTIDE : VIPAGHPVAVRiSEQ ID 400]

PEPTIDE : QVQSYKAKLTPGDVFVIPAG[SEQ ID 401] PEPTIDE : A LTPG DVFVI PAG [SEQ ID 402]

PEPTIDE : HPVAVRASSNLNLLGFGINAE[SEQ ID 403]

PEPTIDE : YKAKLTPGDVFVIPAGHPVAVRJSEQ ID 404]

PEPTIDE : TKNQVQSYKAKLTPGDVFVIPAGfSEQ ID 405]

PEPTIDE : PFNLKSSDPIYS[SEQ ID 406]

PEPTIDE : IEK1LLEE[SEQ ID 407]

PEPTIDE : SRSEPFNLKSSDPIYS[SEQ ID 408]

PEPTIDE : HPVAVRASSNLNL[SEQ ID 409]

PEPTIDE : TLFIPQYTDADFIIWLSGK[SEQ ID 410]

PEPTIDE : NWENVLLGLGVAGSAPGIEGDEIAPLAK[SEQ ID 411]

PEPTIDE : YDQYKDAWDTSVVAEIK[SEQ ID 412]

PEPTIDE : SSFDFIDGYDTPVEGR[SEQ ID 413]

PEPTIDE : GPDTGVDYKDNQIVt[SEQ ID 414]

PEPTIDE : ILNLNNNPYFK[SEQ ID 415]

PEPTIDE : WGTPAYEEfSEQ ID 416]

PEPTIDE ; IDGYDTPVEGR[SEQ ID 41/]

PEPTIDE : VVGTPAYE[SEQ ID 418]

PEPTIDE : lYGPDTGVDYKiSEQ ID 419]

PEPTIDE : VAGSAPGIEGDE[SEQ ID 420]

PEPTIDE : IYGPDTGVDYKDNQ R SEQ ID 421]

PEPTIDE : WGTPAYEE VR[SEQ ID 422]

PEPTIDE : DFIDGYDTPVEGR[SEQ ID 423]

PEPTIDE : LGLGVAGSAPGIEGDEIAPLAK[SEQ ID 424]

PEPTIDE : FNAPLAHLIMAGADVLAVPSR[SEQ ID 425]

PEPTIDE : LGLGVAGSAPGIEGDF[SEQ ID 426]

PEPTIDE : LGLGVAGSAPGIEGDEIAPL[SEQ ID 427]

PEPTIDE : VLTVSPYYAEELISG!AR[SEQ ID 428]

PEPTIDE : EALQAEAGLPVDR[SEQ ID 429]

PEPTIDE : LGLGVAGSAPGlEGDfSEQ ID 430]

PEPTIDE : IMAGADVLAVPSR[SEQ ID 431]

PEPTIDE : GLGVAGSAPGIEGDE[SEQ ID 432]

PEPTIDE : EALQAEAGLPVDRK[SEQ ID 433]

PEPTIDE : TGGLGDVLGGLPPA AANGHRfSEQ ID 434]

PEPTIDE : LEEQKGPDVMA[SEQ ID 435]

PEPTIDE : LGVAGSAPGIEGDEIAPLAK[SEQ ID 436]

PEPTIDE : GLGVAGSAPGIEGDEIAPLAK[SEQ ID 437]

PEPTIDE : TGGLGDVLGGLPPAM[SEQ ID 438]

PEPTIDE : NVLLGLGVAGSAPGIEGDE[SEQ ID 439]

PEPTIDE : TVFDGVLRPGQLfSEQ ID 440]

PEPTIDE : RLQSQ DQRGEII H VK[SEQ ID 441]

PEPTIDE : EGYYGEQQQQPG TR[SEQ ID 442]

PEPTIDE : GYYGEQQQQPGMTR[SEQ ID 443]

PEPTI DE : EEGYYGEQQQQPG TR[SEQ ID 444]

PEPTIDE : YYGGEGSSSEQGYY6EGSSE[SEQ ID 445]

PEPTIDE : YGGEGSSSEQGYYGEG5SE[SEQ ID 446]

PEPTIDE : SSEEGYYGEQQQQPGMTR[SEQ ID 447]

PEPTIDE : SEEGYYGEQQQQPGMTR[SEQ ID 448]

PEPTIDE : QGYYGEGSSEE[SEQ ID 449]

PEPTIDE : YGGEGSSSEQGYYGEGSSEEGYiSEQ ID 450]

PEPTIDE : YGEQQQQPGMTR[SEQ ID 451]

PEPTIDE : YYGEQQQQPGMTR[SEQ ID 452]

PEPTIDE : SYEES PMPLEQGWSSSSSE[SEQ ID 453]

PEPTIDE : YYGEGSSEEGYYGEQQQQPGMTRfSEQ ID 454]

PEPTIDE : QQQQPGMTRV[SEQ ID 455]

PEPTIDE ; GEQQQQPGMTR[SEQ ID 456]

PEPTIDE : SYEESMPMPLEQGWSSSSSEYfSEQ ID 457]

PEPTIDE : YYG G EGSSSEQGYYGEGSSE EG Y [S EQ ID 458] PEPTIDE : YGEQQQQPG MTRVR [SEQ ID 459]

PEPTIDE : GEGSSEEGYYGEQQQQPGMTR(SEQ ID 460]

PEPTIDE : YGEGSSEEGYYGEQQQQPGMTR[SEQ ID 461]

PEPTIDE : QQQQPGMTRVRJSEQ ID 462]

PEPTIDE : QYAAQLPSMCRVEPQQCSIFAAGQYfSEQ ID 463]

PEPTIDE : TVFNGVLRPGQL[SEQ ID 464]

PEPTIDE : TVFNGVLRPGQLLJSEQ ID 465]

PEPTIDE : SGFNNELLSEALGVNALVAK(SEQ ID 466]

PEPTIDE ; NGVLRPGQljSEQ ID 467]

PEPTIDE : ALVAKRLQGQNDQRGE!JSEQ ID 468]

PEPTIDE : VPRYSNTPG [SEQ ID 469]

PEPTIDE : PRYSNTPGMV[SEQ ID 470]

PEPTIDE : YSNTPGMVYfSEQ ID 471]

PEPTIDE : LVPRYSNTPGM[SEQ ID 472]

PEPTIDE : FYNEGDAPW[SEQ ID 473]

PEPTIDE : FYNEGDAPWAL[SEQ ID 474]

PEPTIDE : FEPLRRVRSEAGVTE[SEQ ID 475]

PEPTIDE : FYNE6DAPVVALY(SEQ ID 476]

PEPTIDE ; FYNEGDAPVVAISEQ ID 477]

PEPTIDE : EVEERSQNIF[SEQ ID 478]

PEPTIDE : VEERSQNIFSGF[SEQ ID 479]

PEPTIDE : ASLQEQEQGQVQ[SEQ ID 480]

PEPTIDE ; QEQEQGQVQSR[SEQ ID 481]

PEPTIDE : ASLQEQEQGQVQSR[SEQ ID 482]

PEPTIDE : EVEERSQNIFSGF[SEQ ID 483]

PEPTIDE : VTDLNNGANQLDPRQRD[SEQ ID 484]

PEPTIDE : VEHGLSLLQPYASlfSEQ ID 485]

PEPTIDE : IYVTDLNNGANQLDPRQRDFL[SEQ ID 486]

PEPTIDE : VTDLMNGANQLDPRQRDFL[SEQ ID 487]

PEPTIDE : VEHGLSLLQPYASLQEQEQGQVQSR(SEQ ID 488]

PEPTIDE : VTDLNNGANQLDPR[SEQ ID 489]

PEPTIDE : IYVTDLNNGANQLDPRQRD[SEQ ID 490]

PEPTIDE : YVTDLNNGANQLDPRQRDFL[SEQ ID 491]

PEPTIDE : YVTDLNNGANQLDPR[SEQ ID 492]

PEPTI DE : STELLSEALGVSSQVAR[SEQ ID 493]

PEPTIDE HGLSLLQPYASLQEQE[SEQ ID 494]

PEPTIDE : SGFSTELISEALGVSSQVAR[SEQ ID 495]

PEPTIDE : GAFT LQYKSYQD[S EQ ID 496]

PEPTIDE : GLLLPHYTNGASLVY(SEQ ID 497]

PEPTIDE : FLLAGNKRNPQAYRRE[SEQ ID 498]

PEPTIDE : ALPTDVLANAYR(SEQ ID 499]

PEPTIDE ; DFLLAGN [SEQ ID 500]

PEPTIDE ; DVLANAYR[SEQ ID 501]

PEPTIDE : GAFTPLQYK[SEQ ID 502]

PEPTIDE : QGDVIAI PAGVAHWfSEQ ID 503]

PEPTIDE : FGAFTPLQYKSY[SEQ ID 504]

PEPTIDE : FLLAGNKRNPQAYR[SEQ ID 505]

PEPTIDE : FGAFTPLQYKSYQ[SEQ ID 506]

PEPTIDE : GLSLLQPYASLQEQE[SEQ ID 507]

PEPTIDE ; AFTPLQYK[SEQ ID 508)

PEPTIDE : FG A FTP LQYKSYQD [S EQ ID 509]

PEPTIDE : GDEFGAFTPLQYK[SEQ ID 510]

PEPTIDE : FGAFTPLQYKSYQDV[SEQ ID 511]

PEPTIDE : FGAFTPLQYK[SEQ ID 512]

PEPTIDE : FGAFTPLQYKS[SEQ ID 513]

PEPTIDE : VYIIQGRGITGPTF[SEQ ID 514]

PEPTIDE : YIIQGRGITGPTF[SEQ ID 515] PEPTIDE ; KTNPNSMVSHIAGK[SEQ ID 516]

PEPTIDE : TNPNSMVSHIAGK[SEQ ID 517]

PEPTIDE : PNSMVSHIAGKS[SEQ ID 518]

PEPTIDE ; N I DN P N RADTYN PRAGRVTN [SEQ ID 519]

PEPTIDE ; QR DFLLAGN K [SEQ ID 520]

PEPTIDE : LLQPYAS LQEQE[SE Q ID 521]

PEPTIDE : QRDFLLA6NK[SEQ ID 522]

PEPTIDE : QEQEQGQ QSR[SEQ ID 523]

PEPTIDE : SLLQPYASLQEQE[SEQ ID 524]

PEPTIDE ; ASLQEQEQGQ [SEQ ID 525]

PEPTIDE : ASLQEQEQGQ QSR[SEQ ID 526]

PEPTIDE : DFLLAGN R[SEQ ID 527]

PEPTIDE : QAFEPiRSVRSQAGTTEF[SEQ ID 528]

PEPTIDE : KTNPNSMVSHIAGKSSIF[SEQ ID 529]

PEPTIDE : VRRVIEPRGLLLPHYTNGASL[SEQ ID 530]

PEPTIDE : FGAFTPLQYKSYQDVYN[SEQ ID 531]

PEPTIDE : IALPAGVAHW[SEQ ID 532]

PEPTIDE : RVRQNIDNPNRADTYNPRAGRVTNLfSEQ ID 533]

PEPTIDE : NIDNPN RADTYNPRAGRVTNL[SEQ ID 534]

PEPTIDE : GAFTPLQY SYQDVYN[SEQ ID 535]

PEPTIDE ; PNSMVSHIAGKSSIFR[SEQ ID 535]

PEPTIDE : RLQAFEPIRSVRSQAGTTE[SEQ ID 537]

PEPTIDE ; TNPNS VSHIAG SSIFR[SEQ ID 538]

PEPTIDE : EIGAPDVGHPM [SEQ ID 539]

PEPTIDE : LGAPDVGHPM[SEQ ID 540]

PEPTIDE : ELGAPDVGHP SEVF[SEQ ID 541]

PEPTIDE : ELGAPDV6HPM5[SEQ ID 542]

PEPTIDE ; ELGAPDVGHPMSEVFR[SEQ ID 543]

PEPTIDE : ELGAPDVGHP SEV[SEQ ID 544]

PEPTIDE : ELGAPDVGHPMSE[SEQ ID 545]

PEPTIDE : LGAPDVGHPMSE[SEQ ID 546]

PEPTIDE ; YRELGAPDVGHP SE[SEQ ID 547]

PEPTIDE : LGAPDVGHPMSEV[SEQ ID 548]

PEPTIDE ; RELGAPDVGHPMSE[SEQ ID 549]

PEPTIDE ; APTGTFIASGWVGKD[SEQ ID 550]

PEPTIDE ; LAIVKFSPNEQNKHIGE[SEQ ID 551]

PEPTIDE ; R H Ql TDTTNG HYA P VTYIQVE [SEQ ID 552]

PEPTIDE : GDLAIVKFSPNEQNKHIGE[SEQ ID 553]

PEPTIDE ; NPDNPDNPNNPDNPNNPD1SEQ ID 554]

PEPTIDE : VLDLAIPVNRPGQL [SEQ ID 555]

PEPTIDE : VLDLAIPVNRPGQLQSF [SEQ ID 556]

PEPTIDE : SFLLSGNQNQQNYLS [SEQ ID 557]

PEPTIDE : VLDLAIPVNR [SEQ ID 558]

PEPTIDE : SFLLSGNQNQQNYLSGFS [SEQ ID 559]

PEPTIDE : LAI VN R GQLQS F LLSG [SEQ ID 560]

PEPTIDE : SFLLSGNQNQQNYLSG [SEQ ID 561]

PEPTIDE : LDLAIPVNRPGQL [SEQ ID 562]

PEPTIDE : VLDLAIPVNRPGQLQ [SEQ ID 563]

PEPTIDE : LAIPVNRPGQLQSFLLSGNQNQ [SEQ ID 564]

PEPTIDE : SFLLSGNQNQQNYLSGFSKNILE [SEQ ID 565]

PEPTIDE : GSLLLPHYN [SEQ ID 566]

PEPTIDE : GSLLLPHYNS [SEQ ID 567]

PEPTIDE : SSNLDLLGFG [SEQ I D 568]

PEPTIDE ". AFDLAKNKNQYLRGFS [SEQ ID 569]

PEPTIDE QYLRGFSKNILE [SEQ ID 570]

PEPTIDE : NLLGFGINAE [SEQ ID 571]

PEPTIDE : SNLNLLGFG [SEQ ID 572] PEPTIDE ; LAKNKNQYLRGFSKN [SEQ ID 573]

PEPTIDE : LAKMKNQYLRGFSK [SEQ ID 574]

PEPTIDE : LRGFSKNILE [SEQ ID 57E]

PEPTIDE : YSNKFGKLFE [SEQ ID 576]

PEPTIDE : AFDLAKNKNQYLRGF [SEQ ID 577]

PEPTIDE ; AFDLAKNKNQYLRGFSK [SEQ ID 578]

PEPTIDE : N NQYLRGFS [SEQ ID 579]

PEPTIDE : N NQYLRGFSKNILE [SEQ ID 580]

PEPTIDE : SSNLNLLGFG [SEQ ID 581]

PEPTIDE : EYSNKFGKLFE [SEQ ID 582]

PEPTIDE : ASSNLNLLG [SEQ ID 583]

PEPTIDE : LNLLGFGI [SEQ ID 584]

PEPTIDE ; NKFGKLFE [SEQ ID 585]

PEPTIDE : VQPGRERWEREEDEEQVDE [SEQ ID 586]

PEPTIDE ; RERWEREEDEEQVDE [SEQ ID 587]

PEPTIDE : ASSNLNLLGF (SEQ ID 588]

PEPTIDE : LAKNKNQYLR6FS [SEQ ID 589]

PEPTIDE : ELLGLKNE [SEQ ID 590]

PEPTIDE : ASSNLNLL [SEQ ID 591]

PEPTIOE : YPQLQDLDL (SEQ ID 592]

PEPTIDE : LLGLKNEQQE [SEQ I D 593]

PEPTIDE : LVVLSGKAIL [SEQ ID 594]

PEPTIDE : YDATTAIEAK [SEQ ID 595]

PEPTIDE : NGLQLL PTL [SEQ ID 596]

PEPTIDE ; GLQLL PTL [SEQ ID 597]

PEPTIDE : GVLRPGQLL [SEQ ID 598]

PEPTIDE : DGVLRPGQLL [SEQ ID 599]

PEPTIDE ; LQLL PTLTQQQE [SEQ ID 600]

PEPTIDE : FLLAGNNNR [SEQ ID 601]

PEPTIDE : EFLLAGNNNR [SEQ ID 602]

PEPTIDE : FLLAGNNNRAQQQQVYGSSf E [SEQ ID 603]

PEPTIDE : FLLAGNNNRAQQQQ [SEQ ID 604]

PEPTIDE : FLLAG N RAQQQQVYG [SEQ ID 605]

PEPTIDE : FLLAGNNNRAQQQQVY [SEQ ID 606]

PEPTIDE : FQQQYYPGLSNESESETSE [SEQ ID 607]

PEPTIDE : LSEAL6VNAL (SEQ ID 608]

PEPTIDE ; LRPAFAQQQEQAQQQEQA (SEQ ID 609]

PEPTIDE : LRPAFAQQQE [SEQ ID 610]

PEPTIDE : LRPAFAQQQEQAQQQE (SEQ ID 611]

PEPTIDE : HGLSLLQPYA [SEQ ID 612]

PEPTIDE : HGLSLLQPYASL [SEQ ID 613]

PEPTIDE : HGlSLLQPY [SEQ ID 614]

PEPTIDE : GSLLLPHYN [SEQ ID 615]

PEPTIDE : GSLLLPHYNS [SEQ ID 616]

PEPTIDE : SSNLDLLGFG [SEQ ID 617]

PEPTIDE : ELLGLKNE [SEQ ID 618]

PEPTIDE ; SNLNLLGFG [SEQ ID 619]

PEPTIDE : ASSNLNLL [SEQ ID 620]

PEPTIDE : YPQLQDLDL [SEQ ID 621]

PEPTIDE : SSNLNLLGFG [SEQ ID 622]

PEPTIDE : ASSNLNLLG [SEQ ID 623]

PEPTIDE : LLGLKNEQQE [SEQ ID 624]

PEPTIDE : LVVLSGKAIL [SEQ ID 625]

PEPTIDE : LNLLGFGI (SEQ ID 626]

PEPTIDE I ASSNLNLLGF [SEQ ID 627]

PEPTIDE : LQNYRLLE [SEQ ID 628]

PEPTIDE : LLSGTQNQPSLL [SEQ ID 629] PEPTIDE : LLLPNYNSR [SEQ ID 630)

PEPTIDE : NLQNYRLLE [SEQ ID 631]

PEPTIDE : GSLLLPNYNS [SEQ ID 632] PEPTIDE : NLQNYRLL [SEQ ID 633]

PEPTIDE : NGLQLL PTL [SEQ ID 634] PEPTIDE : GLQLLKPTL [SEQ I D 635]

PEPTIDE : GVLRPGQLL [SEQ ID 636] PEPTIDE : DGVLRPGQLL [SEQ ID 637] PEPTIDE : LQILKPTLTQQQE [SEQ ID 638]

PEPTIDE : LSEALGVNAL [SEQ ID 639] PEPTIDE : LNSQKFPILNLVQLSATR [SEQ ID 640] PEPTIDE : HGLSLLQPYA [SEQ ID 641] PEPTIDE : HGLSLLQPYASL [SEQ ID 642] PEPTIDE : HGLSLLQPY [SEQ ID 643] PEPTIDE : DKIILGPK [SEQ ID 644]

PEPTIDE : DRKRRQQGEETDAIVK [SEQ ID 645] PEPTIDE : IGINGFSRIGRLVAR [SEQ ID 646] PEPTIDE ; ILNRGHKIKGTVVL [SEQ ID 647] PEPTIDE : INGFGRIGRLVAR (SEQ ID 648] PEPTIDE : KKNEPWWPK [SEQ ID 649] PEPTIDE : LLLLGIIFI ASVV [SEQ ID 650] PEPTIDE : RLLQKFDQRSKIF [SEQ ID 651] PEPTIDE : TIKSRFPLLLLLG [SEQ ID 652] PEPTIDE : TKAVKNTVG AL [SEQ ID 653] PEPTIDE : VIVKLSR [SEQ ID 654]

PEPTIDE : HSPR (SEQ ID 655]

PEPTIDE : HWF [SEQ ID 655]

PEPTIDE : IFEDAITIPGR (SEQ I D 657] PEPTIDE : ELTFPGSVQE [SEQ ID 658] PEPTIDE ; ELTFPGSVQ [SEQ ID 659] PEPTIDE : DSINALEPDHR [SEQ ID 660] PEPTIDE : LDALEPDNRIESE [SEQ ID 661] PEPTIDE : EEGIQLVAEAIR [SEQ ID 662] PEPTIDE I TFAEETWGK [SEQ ID 663] PEPTIDE : LVSHPIAAHEGR [SEQ ID 664] PEPTIDE : NLAQAPAQALL [SEQ ID 665] PEPTIDE : ILVDGSHDIER [SEQ ID 666] PEPTIDE ; LDVTPLSLGL [SEQ ID 667] PEPTIDE : WTIVQGLPIDE [SEQ ID 668] PEPTIDE : KTLDYWPSLR [SEQ ID 669] PEPTIDE : RHGEWGPSY [SEQ ID 670] PEPTIDE : H PP [SEQ ID 671]

PEPTIDE : HMPS(SEQ ID 672]

PEPTIDE : MPPSS[SEQ ID 673]

PEPTIDE :PRRF [SEQ ID 674]

PEPTIDE : FHMP [SEQ ID 675]

PEPTIDE : NNPF [SEQ ID 676]

PEPTIDE : FWM [SEQ ID 677]

PEPTIDE : PHMP [SEQ ID 678]

PEPTIDE ; FHMPP [SEQ ID 679]

PEPTIDE : HMPSS [SEQ ID 680]

PEPTIDE : HRRS [SEQ ID 681]

PEPTIDE : MPPS [SEQ ID 682]

PEPTIDE :: MPRR [SEQ ID 683]

PEPTIDE : PHMPS [SEQ ID 684] PEPTIDE I HGGEGGRPYJSEQ ID 685)

PEPTIDE : GYP YPLPR [SEQ ID 686]

PEPTIDE ; LQQAPPPPQR [SEQ ID 687]

PEPTIDE ; VGWGEQPWSPY [SEQ !D 688]

PEPTIDE ; HPRPPKPDAPR [SEQ ID 689]

PEPTIDE : FWN [SEQ ID 690]

PEPTIDE : MRFR [SEQ ID 691]

PEPTIDE : WHT [SEQ ID 692]

PEPTIDE : FRRP [SEQ ID 693]

PEPTIDE : HRFR [SEQ ID 694]

PEPTIDE : FRR [SEQ ID 695]

PEPTIDE : MFRRP [SEQ ID 696]

PEPTIDE : N PS [SEQ ID 697]

PEPTIDE : WM [SEQ ID 698]

PEPTIDE : YSLKPLVPR [SEQ ID 699]

PEPTIDE : PVEMPTLLYPS [SEQ ID 700]

PEPTIDE : QSFLLSGNQ [SEQ ID 701]

PEPTIDE : SLTLEDVPNHGTIR [SEQ ID 702]

PEPTIDE : LSLTDL [SEQ ID 703]

PEPTIDE : THPMNFLNER [SEQ ID 704]

PEPTIDE : LGLSPQDALK [SEQ ID 70S]

PEPTIDE : TRPPVPSTIPTK [SEQ ID 706]

PEPTIDE : RGPQQYAEWQINE [SEQ ID 707]

PEPTIDE : GIARLAGTSSVIN [SEQ ID 708]

PEPTIDE : YLRGFS [SEQ ID 709]

PEPTIDE : LRGFSK [SEQ ID 710]

PEPTIDE: GALMLPHYNSR [SEQ ID 711]

PEPTIDE: GAL LPHYN [SEQ ID 712]

PEPTIDE: RSQNIF [SEQ ID 713]

PEPTIDE: GHP [SEQ ID 714]

PEPTIDE: WDP [[SEQ ID 715]

PEPTIDE: WHN [SEQ ID 716]

PEPTIDE; P PL [SEQ ID 717]

PEPTIDE: HNPR [SEQ ID 718]

PEPTIDE: HPSF [SEQ ID 719]

PEPTIDE: PNSM [SEQ ID 720]

PEPTIDE: HPMS [SEQ ID 721]

PEPTIDE: PMP [SEQ ID 722]

PEPTIDE: VFDGVLRPG [SEQ ID 723]

PEPTIDE: RLQSQNDQRG [SEQ ID 724]

PEPTIDE: LQSQND [SEQ ID 725]

PEPTIDE: LEPDNR [SEQ ID 726]

PEPTIDE: QSQNDQRGEIIHVK [SEQ ID 727]

PEPTIDE: RGEI1HVK [SEQ ID 728]

PEPTIDE: RLQSQNDQ [SEQ ID 729]

PEPTIDE; RLQSQNDQRGEHH [SEQ ID 730]

PEPTIDE: LQSQNDQRGEI [SEQ ID 731]

PEPTIDE: FLPQHTD [SEQ ID 732]

PEPTIDE: PQQYAEWQ [SEQ ID 733)

PEPTIDE: QSFLLSGNQNQQ [SEQ ID 734]

PEPTIDE: QSFLLSGNQ [SEQ ID 735]

PEPTIDE: PGQLQSFLLSGN [SEQ ID 736]

PEPTIDE: PGQLQSFLLSGNQNQQNYLSGF [SEQ ID 737]

PEPTIDE: QLQSFLLSGNQNQQNYLSGFSK [SEQ ID 738]

PEPTIDE: QNQQNYLSGFSK [SEQ ID 739]

PEPTIDE: GPQQYAEWQINE [SEQ ID 740]

PEPTIDE: RGPQQYA [SEQ ID 741] PEPTIDE: EWQINEK [SEQ ID 742)

PEPTIDE: GKIKIGINGFGR1GRLVA [SEQ ID 743]

PEPTIDE: MMAP [SEQ ID 744]

PEPTIDE; MAPH [SEQ ID 745]

PEPTIDE: ERGVLY (SEQ ID 746]

PEPTIDE: RVLNGL [SEQ ID 747]

PEPTIDE: SLLSGE [SEQ ID 748]

PEPTIDE: LLSGED [SEQ ID 749]

PEPTIDE: LSGEDA [SEQ ID 750]

PEPTIDE: HRHA [SEQ ID 751]

PEPTIDE : SRA1VIVTVNE [SEQ ID 752]

PEPTIDE : AKLTPGDV [SEQ ID 753]

PEPTIDE : IVIVTVNEGK [SEQ ID 754]

PEPTIDE : LDALEPONRIE5EGGL (also in P02857) [SEQ ID 755]

PEPTIDE : RPYYSNAPQE (also in P028S7) [SEQ ID 756]

PEPTIDE : LDALEPDNRIESEGGLIETWNPNNK (also in P02857) [SEQ ID 757]

PEPTIDE : AIV1VTVNEGK (also in P13918) [SEQ ID 758]

PEPTIDE : LQVVNCNGNTVFOGEL [SEQ ID 759]

PEPTIDE : QWNCNGNTVFDGEL [SEQ ID 760]

PEPTIDE : IIAVPTGIVF [SEQ ID 761]

PEPTIDE : GRRYRDRHQ VNRFRE [SEQ ID 762]

PEPTIDE : RPYYSNAPQEI [SEQ ID 763]

PEPTIDE ; RLDALEPDNRIE [SEQ ID 764]

PEPTIDE : RLDALEPDNRIESE [SEQ ID 765]

PEPTIDE : LDALEPDNRIESEGGLIETW [SEQ ID 766]

PEPTIDE : LDALEPDNRIE [SEQ ID 767]

PEPTIDE : LDALEPDNRIESEGGLIE [SEQ ID 768)

PEPTIDE : LDALEPDNRIESEGGL (also in P02855) [SEQ ID 769]

PEPTIDE : RPYYSNAPQE (also in P02857) [SEQ ID 770]

PEPTIDE : LDALEPDNRIESEGGLIETWNPNNK (also in P02855) [SEQ ID 771]

PEPTIDE : VEHGLSLLQPYASLQEQEQGQVQSRER [SEQ ID 772]

PEPTIDE : RSQNIFSGF [SEQ ID 773]

PEPTIDE : GITGPTFPGCPESY [SEQ ID 774]

PEPTIDE : CNGS [SEQ ID 775]

PEPTIDE : SPREC {SEQ ID 776]

PEPTIDE : PREC [SEQ ID 777]

PEPTIDE : PRECR [SEQ ID 778]

PEPTIDE : CPES [SEQ ID 779]

PEPTIDE : SGCS [SEQ ID 780]

PEPTIDE : CSNG [SEQ ID 781]

PEPTIDE : RSQNIFSGFSTE [SEQ ID 782]

PEPTIDE : VEEWSQNIFSGFST [SEQ ID 783]

PEPTIDE : WSQ IFSGFSTEL [SEQ ID 784]

PEPTIDE : WSQNIFSGFSTE [SEQ ID 785]

PEPTIDE : STSQWQSSRR [SEQ ID 786)

PEPTIDE : NRPI [SEQ ID 787]

PEPTIDE : CDGS [SEQ ID 788]

PEPTIDE : PRGC [SEQ ID 789]

PEPTIDE : PRGCR [SEQ ID 790]

PEPTIDE : RGCR [SEQ ID 791]

PEPTIDE : GCRF [SEQ ID 792]

PEPTIDE : PTFP[SEQ ID 793]

PEPTIDE : PGCPE [SEQ ID 794]

PEPTIDE : GCPE [SEQ ID 795]

PEPTIDE : CPET [SEQ ID 796]

PEPTIDE : AHWC [SEQ ID 797]

PEPTIDE : HWCY [SEQ ID 798] PEPTIDE : SGCP [SEQ ID 799]

PEPTIDE : SGCPN [SEQ ID 800]

PEPTIDE : GCPN [SEQ ID 801]

PEPTIDE : CPNG [SEQ ID 802]

PEPTIDE : TFCTM [SEQ ID 803]

PEPTIDE : FCTM [SEQ ID 804]

PEPTIDE : FCTMR [SEQ ID 80S]

PEPTIDE : CTMR [SEQ ID 806]

PEPTIDE : EGCA [SEQ ID 807]

PEPTIDE ; SQNIFSGFSTELL [SEQ ID 808]

PEPTIDE : SQNIFSGFSTE [SEQ ID 809]

PEPTIDE : QNDQRGEIVR [SEQ ID 810]

PEPTIDE : SQNIFSGFSTEL (also in P07730) [SEQ ID 811]

PEPTIDE : QLQCQNDQRGEI (also in P07730) [SEQ ID 812]

PEPTIDE : LGQSTSQWQSSR (also in P07730) [SEQ ID 813]

PEPTIDE : QQLLGQSTSQWQSSR (also In P07730) [SEQ ID 814]

PEPTIDE : LLGQSTSQWQSSR (also In P07730) [SEQ ID 815]

PEPTIDE : NDQRGEIVR [SEQ I D 816]

PEPTIDE : GQSTSQWQSSR [SEQ ID 817]

PEPTIDE : STSQWQSSR [SEQ ID 818]

PEPTIDE : GITGPTFPGCPET (SEQ ID 819]

PEPTIDE : GITGPTFPGCPETY [SEQ ID 820]

PEPTIDE : SQNIFSGFSTEL (also in P07728) [SEQ ID 821]

PEPTIDE : QLQCQNDQRGEI (also in P07728) [SEQ ID 822]

PEPTIDE : LGQSTSQWQSSR (also in P07728) [SEQ ID 823]

PEPTIDE : QQLLGQSTSQWQSSR (also in P07728) [SEQ ID 824)

PEPTIDE : LLGQSTSQWQSSR (also in P07728) [SEQ ID 825]

PEPTIDE ; IFFA QTYL [SEQ ID 826]

PEPTIDE : EHLEPNLEGLTVEE [SEQ ID 827]

PEPTIDE : IFFANQTYLPSETPAPLVHYREEELNNLRGDGTGER [SEQ ID 828]

PEPTIDE : IMFEWDDDMGIPGAFYI [SEQ ID 829]

PEPTIDE : 1FFANQTYLPSETPAPLVHYREEELNNLR [SEQ ID 830]

PEPTIDE : TEQALPADLIK [SEQ ID 831]

PEPTIDE ; EHLEP LEGLTVEEAIQNKK [SEQ ID 832]

PEPTIDE : ISKEHLEPNLEGLTVEEA1QNKK (SEQ ID 833]

PEPTIDE : LSLPHPQGDEHGAVSY [SEQ ID 834)

PEPTIDE : IS EHLEPNLEGLTVEEAIQNK [SEQ ID 835]

PEPTIDE : EHLEPNLEGLTVEEAIQNK [SEQ ID 836]

PEPTIDE : LSTTGGNSGSPVFNEKNE [SEQ ID 837]

PEPTIDE : QSFLLSGNQNQQNYLSG [SEQ ID 838]

PEPTIDE : VLDLAIPVNRPGQLQS [SEQ ID 839]

PEPTIDE : VLDLAIPVNRPGQLQSFL [SEQ ID 840]

PEPTIOE : FLLSGNQNQQNYLSG [SEQ ID 841]

PEPTIDE : FLLSGNQNQQNYLSGFSK [SEQ ID 842]

PEPTIDE ; DPQN FIFKSNKFQTLFE [SEQ ID 843]

PEPTIDE : ELAFPGSAQEVDRILENQK [SEQ ID 844]

PEPTIDE : AIVIVTVN EGK (also in P02855) [SEQ ID 845]

PEPTIDE : INAVAA RLQSQNDQRGE [SEQ ID 846]

PEPTIDE : NRAQQQQVYGSSIE [SEQ ID 847]

PEPTIDE : PS 1 NPWHSPR [SEQ ID 848]

PEPTIDE : CHGS [SEQ ID 849]

PEPTIDE : CHGSM [SEQ ID 850]

PEPTIDE : PWHS [SEQ ID 851]

PEPTIDE : FREC [SEQ ID 852]

PEPTIDE ; RECR [SEQ ID 853]

PEPTIDE : ECRF [SEQ ID 854] PEPTIDE : CRFD [SEQ ID 855]

PEPTIDE : CRFDR [SEQ ID 856]

PEPTIDE : CTGT [SEQ ID 857]

PEPTIDE : FPGC [SEQ ID 858]

PEPTIDE : FPGCP [SEQ ID 859]

PEPTIDE : PGCP [SEQ ID 860]

PEPTIDE : PGCPA [SEQ ID 861]

PEPTIDE : PGCPAT [SEQ ID 862]

PEPTIDE : GCPA [SEQ ID 863]

PEPTIDE : CPAT [SEQ ID 864]

PEPTIDE : ENFC [SEQ ID 865]

PEPTIDE : NFCT [SEQ ID 866]

PEPTIDE : IMFCTI [SEQ ID 867]

PEPTIDE I FCTI [SEQ ID 868]

PEPTIDE : AQQQQVVG SS I E QH [SEQ ID 869]

PEPTIDE : AQQQQVYGSSIEQHSGQNIFSGF [SEQ ID 870]

PEPTIDE ; AAKRLQSQNDQRGE [SEQ ID 871]

PEPTIDE : QARSLKNNRGEE (also in P14614) [SEQ ID 8721

PEPTIDE ; FNPSTNPWHSPRQGS (also in Q0DEV5) (SEQ ID 873]

PEPTIDE : QARSLKNNRGEE (also in P14323) [SEQ ID 874]

PEPTIDE : AAASLPAFCNVDIPNGGGGVCYWLAR [SEQ ID 87S]

PEPTIDE : VAGSAPGIEGDEIAPLAK [SEQ ID 876]

PEPTIDE : LGVAGSAPGIEGDEIAPLAKEN [SEQ ID 877]

PEPTIDE : GSAPGIEGDEIAPLAKE [SEQ ID 878]

PEPTIDE : VAGSAPGIEGDEIAP [SEQ ID 879]

PEPTIDE ; GVAGSAPGIEGDEIAPLAK [SEQ ID 880]

PEPTIDE : GVAGSAPGI EG DE I A LAKE N [SEQ ID 881]

PEPTIDE I VAGSAPGIEGDEIAPLAKEN [SEQ ID 882]

PEPTIDE : SAPGIEGDEIAPLAK [SEQ ID 883]

PEPTIDE : GSAPGIEGDEIAPLAK (SEQ ID 884]

PEPTIDE : SAPGIEGDEIAPLAKEN [SEQ ID 885]

PEPTIDE : FNPSTNPWHSPRQGS (also In P14323) [SEQ ID 886]

PEPTIDE : VDLVIPVNGPGK [SEQ ID 887]

PEPTIDE : LVDLVIPVNGPGK [SEQ ID 888]

PEPTIDE : IKLPAGTTSY [SEQ ID 889]

PEPTIDE : IKLPAGTTSYL [SEQ ID 890]

PEPTIDE : RRNPFLFKSNKF [SEQ ID 891]

PEPTIDE : IENPVKELTFPGSVQEINR [SEQ ID 892]

PEPTIDE : RRNPFLFKSNKFLT [SEQ ID 893]

PEPTIDE : AKPHTIFLPQHIDA [SEQ ID 894]

PEPTIDE : AKPHTIFLPQHIDAD [SEQ ID 895]

PEPTIDE : KQKYRYQRE [SEQ ID 896]

PEPTIDE : KQKYQYQRE [SEQ ID 897]

PEPTIDE : MLPH [SEQ ID 898]

PEPTIDE : RRNPFLFKSNKFLTLFENE [SEQ ID 899]

PEPTIDE : PFLFKSNKFLTLFE [SEQ ID 900]

PEPTIDE : SQERRNPFLFKSNKFLTLFE [SEQ ID 901]

PEPTIDE : RRNPFLFKSNKFLTLFE [SEQ ID 902]

PEPTIDE : SQERRNPFLFKSNKFLTLFENE [SEQ ID 903]

PEPTIDE : LTFPGSVQE [SEQ ID 904]

PEPTIDE ; ELTFPGSVQEINR (SEQ ID 905]

PEPTIDE : KNPQLQDLDI [SEQ ID 906]

PEPTIDE : GQSTSQWQSSR [SEQ ID 907]

PEPTIDE : QSTSQWQSSR (also in P07728) [SEQ ID 908]

PEPTIDE : QSTSQWQSSR (also in P07730) [SEQ ID 909]

PEPTIDE : EEEEQGEEEINK [SEQ ID 910]

PEPTIDE : PSTNPWHSPR [SEQ ID 911] PEPTIDE : AQAQDQYQQVQYSE [SEQ ID 912]

PEPTIDE : SEAGVTEYFDEKNELFQCTGTFVIRR [SEQ ID 913]

PEPTIDE ; QAQAQDQYQQVQYSE [SEQ ID 914]

PEPTIDE : GSMGLTFPGCPAT (also in P14614) [SEQ ID 915]

PEPTIDE : GS GLTFPGCPATY (also in P14614) [SEQ ID 916]

PEPTIDE : LGAFTPRY [SEQ ID 917]

PEPTIDE : LGAFTPRYQQ [SEQ ID 918]

PEPTIDE ; ALGVNALVAKRLQGQN [SEQ ID 919]

PEPTIDE : LGAFTPRYQ [SEQ ID 920]

PEPTIDE ; GSMGLTFPGCPAT (also In P14323) [SEQ ID 921]

PEPTIDE : GSMGLTFPGCPATY (also in P14323) (SEQ ID 922]

PEPTIDE ; SNNPFKFLVPARQS [SEQ ID 923]

PEPTIDE : CAGVFVIRR [SEQ ID 924]

PEPTIDE : GSPLQSPRGF [SEQ ID 925]

PEPTIDE : RSSWQQQSY [SEQ ID 926]

PEPTIDE : SFGGSPLQSPR [SEQ ID 927]

PEPTIDE : YLPTKQLQPTW [SEQ ID 928]

PEPTIDE : G PRSSWQQQ [SEQ ID 929]

PEPTIDE ; FGGSPLQSPRG [SEQ ID 930]

PEPTIDE : LNLLGFGINAENNE [SEQ ID 931]

PEPTIDE I SGPFNLRSRNPIYSNKFGKFFE [SEQ ID 932]

PEPTIDE : TSKQVQLYKAKLSPGDVFVIPAG [SEQ ID 933]

PEPTIDE : GHIRLLQKFDKRSKIFE [SEQ ID 934]

PEPTIDE : TSKQVQLYKAKLSPG DVF I PAG H P [SEQ ID 935]

PEPTIDE I TSKQVQLYKAKLSPG DVF VI PAG H PV [SEQ ID 936] PEPTIDE : TSKQVQLYKAKLSPG DVF VI PAG H PVA [SEQ ID 937] PEPTIDE : TSKQVQLYKAKLSPGDVFVIPAGH PVAI [SEQ ID 938] PEPTIDE : TS KQVQLYKAKLSPG DVFVI PAG H PVAI [SEQ ID 939] PEPTIDE : KFKDEHQKIHRFRQGDVIALPAGVAHW [SEQ ID 940] PEPTIDE : KFKDEHQKIHRFRQGDVIALPAGVAHWC [SEQ ID 941] PEPTIDE : KFKDEHQKIHRFRQGDVIALPAGVAHWCY [SEQ ID 942] PEPTIDE ; SPFWNINAHSVVYITQGRARVQVVNNNGK [SEQ ID 943] PEPTIDE ; QKIHRFRQGDVIALPAGVAHW [SEQ ID 9441

PEPTIDE : VVRRVIEPRGLLLPHYTNG [SEQ ID 945]

PEPTIDE : VRRVIEPRGLLLPHYTNG [SEQ ID 946]

PEPTIDE : IRLLQKFDQRS IFE [SEQ ID 947]

PEPTIDE : AVAAKRLQSQNDQRGEIIHVKNGLQ [SEQ ID 948] PEPTIDE : VAAKRLQSQNDQRGEI1HVKNGLQ [SEQ ID 949] PEPTIDE : TVFDGVLRPGQL1 IIPQHYAVLKK [SEQ ID 950] PEPTIDE : PSTNPWHSPR [SEQ ID 951]

PEPTI DE : NPSTNPWHSPRQGSFR [SEQ ID 952]

PEPTIDE : QLFNPSTNPWH5PRQGSFR [SEQ ID 953]

PEPTIDE : SMAQLFNPSTNPWHSPRQGSFR [SEQ ID 954] PEPTIDE : QLFNPSTNPWHSPRQGSFRECRF [SEQ ID 955] PEPTIDE : CHGSMAQLFNPSTNPWHSPRQGSFR [SEQ ID 956] PEPTIDE : CHGSMAQLFNPSTNPWHSPRQGSFRECRF [SEQ ID 957] PEPTIDE : LLLCHGSMAQLFNPSTNPWHSPRQGSFR [SEQ ID 958] PEPTIDE : PSTNPWHSPRQGSFRE [SEQ ID 9591

PEPTIDE : PWHSPRQGSFRE [SEQ ID 960]

PEPTIDE : QLFNPSTNPWHSPRQGSF [SEQ ID 961]

PEPTIDE : RVIQPQGLLVPR (SEQ ID 962]

PEPTIDE : FNPSTNPWHSPRQGSF [SEQ ID 963]

PEPTIDE : FNPSTNPWHSPRQGS [SEQ ID 964]

PEPTIDE : GPNVNPWHNPRQG6FRECR [SEQ ID 965]

PEPTIDE : QLFGPNVNPWHNPRQGGFR (SEQ ID 966]

PEPTIDE : QLFGPNVNPWHNPRQGGFRECR [SEQ ID 967] PEPTIDE : SMAQLFGPNVNPWHNPRQGGFR [SEQ ID 968] PEPTIDE ; CHGSMAQLFGPNVNPWHNPRQGGFR [SEQ ID 969] PEPTIDE : SMAQLFGPNVNPWHNPRQGGFRECR {SEQ ID 970] PEPTIDE : LLLCHGSMAQLFGPNVNPWHNPRQGGFR [SEQ ID 971] PEPTIDE : WRPSYE EE [SEQ ID 972]

PEPTIDE : A PHTIFLPQHIDADLILVVLSG AILTVLSPNDR [SEQ ID 973] PEPTIDE : PRVPAQRERGRQEGE EE RHGEWRP [SEQ ID 974] PEPTIDE : PRVPAQRERGRQEGE EEKRHGEWRPS [SEQ ID 975] PEPTIDE : PRVPAQRERGRQEGEKEEKRHGEWRPSY [SEQ ID 976] PEPTIDE : PRVPAQRERGRQEGEKEEKRHGEWR [SEQ ID 977] PEPTIDE : GSEPRVPAQRERGRQEGEKEEKRHGEWRP [SEQ ID 978] PEPTIDE : RHGEWRPSYEK [SEQ ID 979]

PEPTIDE : KKEQKEVQPGRFRW [SEQ ID 980]

PEPTIDE : KKEQ EVQPGRERWER [SEQ ID 981]

PEPTIDE : REK EQ EVQPGRERW [SEQ ID 982]

PEPTIDE : QREKKEQKEVQPGRERW [SEQ ID 983)

PEPTIDE : REKKEQKEVQPGRERWER {SEQ ID 984]

PEPTIDE : QREKKEQKEVQPGRERWER [SEQ ID 985]

PEPTIDE : QYQREKKEQKEVQPGRER [SEQ ID 986]

PEPTIDE : YQYQRE KEQKEVQPGRERW [SEQ ID 987]

PEPTIDE ; QYQREKKEQ EVQPGRER ER [SEQ ID 988]

PEPTIDE : QKYQYQREK EQ EVQPGRERW (SEQ ID 989]

PEPTIDE : YQYQREKKEQKEVQPGRERWER [SEQ ID 990]

PEPTIDE : KQKYQYQRE KEQ EVQPGRERW [SEQ ID 991] PEPTIDE ; QKYQYQREKKEQKEVQPGRERWE [SEQ ID 992] PEPTIDE : KQKYQYQREKKEQKEVQPGRERWE (SEQ ID 993] PEPTIDE ; QKYQYQREK EQ EVQPGRERWER [SEQ ID 994) PEPTIDE : E E KQKYQYQR EKKEQKEVQPGRERW [SEQ ID 995] PEPTIDE : KQKYQYQREKKEQKEVQPGRERWER [SEQ ID 996] PEPTIDE : QKYQYQREKKEQKEVQPGRERWERE [SEQ ID 997] PEPTIDE : KQKYQYQREKKEQKEVQPGRERWERE [SEQ ID 998] PEPTIDE ; EEKQKYQYQRE EQ EVQPGRERWER [SEQ ID 999] PEPTIDE : KQKYQYQREKKEQKEVQPGRERWERE E [SEQ ID 1000] PEPTIDE : PINLRSHKPEYSNKFGKLFE!TPEKKYP [SEQ ID 1001] PEPTIDE : KRHGEWRPSY [SEQ ID 1002]

PEPTIDE : PAQRERGRQEGEKEEKRHGEWRP [SEQ ID 1003] PEPTIDE : PAQRERGRQEGEKEEKRHGEWRPS [SEQ I D 1004] PEPTIDE : PRVPAQRERGRQEGEKEEKRHGEW [SEQ ID 1005] PEPTIDE : EWRGSQRREDPEERARLRHREERTK [SEQ ID 1006] PEPTIDE ; PAQRERGRQEGEKEEKRHGEWRPSY [SEQ ID 1007] PEPTIDE : EWRGSQRREDPEERARLRHREERTKR [SEQ ID 1008] PEPTIDE : PAQRERGRQEGEKEEKRHGEWRPSYE [SEQ ID 1009] PEPTIDE : EEWRGSQRREDPEERARLRHREERTKR [SEQ ID 1010] PEPTIDE : EWRGSQRREDPEERARLRHREERTKRD [SEQ ID 1011] PEPTIDE : GSEPRVPAQRERGRQEGEKEEKRHGEW [SEQ ID 1012] PEPTIDE : PAQRER6RQEGEKEEKRHGEWRPSYEK [SEQ ID 1013] PEPTIDE : EWRGSQRREDPEERARLRHREERTKRDR [SEQ ID 1014] PEPTIDE : 6SEPRVPAQRERGRQEGEKEEKRHGEWR [SEQ ID 1015] PEPTIDE : PAQRERGRQEGEKEEKRHGEWRPSYEKE (SEQ ID 1016] PEPTIDE : EEWRGSQRREDPEERARLRHREERTKRDR [SEQ ID 1017] PEPTIDE : EWRGSQRREDPEERARI.RHREERTKRDRR [SEQ ID 1018] PEPTIDE : KEEKRHGEWRP [SEQ ID 1019]

PEPTIDE : KEEKRHGEWRPS [SEQ ID 1020]

PEPTIDE : GEKEEKRHGEWRP [SEQ ID 1021]

PEPTIDE : KEEKRHGEWRPSY [SEQ ID 1022)

PEPTIDE : KEQKEVQPGRERW [SEQ ID 1023]

PEPTIDE : KRHGEWRPSYEKE [SEQ ID 1024]

PEPTIDE : EEKRHGEWRPSYEK [SEQ ID 1025] PEPTIDE : GEKEEKRHGEWRPS [SEQ ID 1026]

PEPTIDE : EEKRHGEWRPSYE [SEQ ID 1027]

PEPTIDE ; KEQKEVQPGRERWE [SEQ ID 1028]

PEPTIDE ; EE RHGEWRPSYEKQ [SEQ ID 1029]

PEPTIDE : GEKEEKRHGEWRPSY [SEQ ID 1030]

PEPTIDE : KEEKRHGEWRPSYEK [SEQ ID 1031]

PEPTIDE : KEQKEVQPGRERWER [SEQ ID 1032]

PEPTIDE ; EQKEVQPGRERWE [SEQ ID 1033]

PEPTIDE : KEEKRHGEWRPSYEKE [SEQ ID 1034]

PEPTIDE : KEQKEVQPGRERWERE [SEQ ID 1035]

PEPTIDE : RQEGEKEEKRHGEWRP [SEQ ID 1036]

PEPTIDE : GEKEEKRHGEWRPSYEK [SEQ ID 1037]

PEPTIDE : GRQEGEKEE RHGEWRP [SEQ ID 1038]

PEPTIDE : KKEQKEVQPGRERWERE [SEQ ID 1039]

PEPTIDE : REKKEQKEVQPGRERWE [SEQ ID 1040]

PEPTIDE : RQEGEKbE RHGEWRPS [SEQ ID 1041]

PEPTIDE : GEKEEKRHGEWRPSYEKQ [SEQ ID 1042]

PEPTIDE : GRQEGEKEEKRHGEWRPS [SEQ ID 1043]

PEPTIDE ; KKEQKEVQPGRERWEREE [SEQ ID 1044]

PEPTID : QREKKEQKEVQPGRERWE [SEQ ID 1045]

PEPTIDE ; RQEGE EE RHGEWRPSY [SEQ ID 1046]

PEPTIDE ; ERGRQEGEKEEKRHGEWRP [SEQ ID 1047]

PEPTIDE ; GRQEGEKE KRHGEWRPSY [SEQ ID 1048]

PEPTIDE ; REKKEQKEVQPGRERWERE [SEQ ID 1049]

PEPTIDE : ERGRQEGEKEEKRHGEWRPS [SEQ ID 1050] PEPTIDE : QREKKEQKEVQPGRERWERE [SEQ ID 1051] PEPTIDE : QYQREKKEQKEVQPGRERWE [SEQ ID 1052] PEPTIDE : REKKEQKEVQPGRERWEREE (SEQ ID 1053] PEPTIDE : RERGRQEGEKEEKRHGEWRP [SEQ ID 1054] PEPTIDE ·. RQEGE EEKRHGEWRPSYEK [SEQ ID 1055] PEPTIDE : ERGRQEGEKEEKRHGEWRPSY [SEQ ID 1056] PEPTIDE : GRQEGEKEEKRHGEWRPSYEK [SEQ ID 1057] PEPTIDE : PAQRERGRQEGEKEEKRHGEW [SEQ ID 1058] PEPTIDE : QREKKEQ EVQPGRERWEREE (SEQ ID 1059] PEPTIDE : RERGRQEGEKEEKRHGEWRPS [SEQ ID 1060] PEPTIDE : RQEGE EEKRHGEWRPSYEKQ [SEQ ID 1061] PEPTIDE : YQYQREKKEQKEVQPGRERWE [SEQ ID 1062] PEPTIDE ; GQRERGRQEGEKEEKRHGEWRP [SEQ ID 1063] PEPTIDE : PAQRERGRQEGEKEEKRHGEWR (SEQ ID 1064] PEPTIDE : QYQREKKEQ EVQPGRERWERE [SEQ ID 1065] PEPTIDE : RERGRQEGEKEEKRHGE RPSY [SEQ ID 1066] PEPTIDE : ERGRQEGEKEEKRHGEWRPSYEK [SEQ ID 1067] PEPTIDE ; GQRERGRQEGEKEEKRHGEWRPS [SEQ ID 1068] PEPTIDE : QYQRE KEQKEVQPGRERWEREE [SEQ ID 1069] PEPTIDE : RERGRQEGEKEEKRHGEWRPSYE [SEQ ID 1070] PEPTIDE : YQYQREKKEQKEVQPGRERWERE [SEQ ID 1071] PEPTIDE : ERGRQEGEKEEKRHGEWRPSYEKQ [SEQ ID 1072] PEPTIDE : GQRERGRQEGEKEEKRHGEWRPSY [SEQ ID 1073] PEPTIDE : RERGRQEGEKEE RHGEWRPSYEK [SEQ ID 1074] PEPTIDE : YQYQR E K EQKEVQPG R ERWE EE {SEQ ID 1075] PEPTIDE I GQRERGRQEGEKEEKRHGEWRPSYE [SEQ ID 1076] PEPTIDE ; RERGRQEGEKEEKRHGEWRPSYEKE [SEQ ID 1077) PEPTIDE : RHGEWRPSYE QEDEEEKQKYRYQR [SEQ ID 1078] PEPTIDE : EEEKQKYQYQREKKEQKEVQPGRERW [SEQ ID 1079] PEPTIDE : GQRERGRQEGEKEEKRHGEWRPSYEK [SEQ ID 1080] PEPTIDE : QKYQYQREKKEQKEVQPGRERWEREE [SEQ ID 1081] PEPTIDE : EEEKQKYQYQREKKEQKEVQPGRERWE [SEQ ID 1082] PEPTIDE ; GQRERGRQEGEKEEKRHGEWRPSYEKQ [SEQ ID 1083] PEPTIDE : QKYQYQREK EQKEVQPGRERWEREED [SEQ ID 1084] PEPTIDE ; RHGEWRPSYEKQEDEEEKQKYRYQREK [SEQ ID 1085] PEPTIDE : EEEKQKYQYQREKKEQKEVQPGRERWER (SEQ ID 1086] PEPTIDE ; EEKQKYQYQREKKEQKEVQPGRERWERE [SEQ ID 1087] PEPTIDE : GQRERGRQEGEKEEKRHGEWRPSYEKQE [SEQ ID 1088] PEPTIDE : KQKYQYQREKKEQKEVQPGRERWEREED [SEQ ID 1089] PEPTIDE : PSEFEPINLRSHKPEYSNKFGKLFEITP [SEQ ID 1090]

PEPTIDE : EEEKQKYQYQRE KEQKEVQPGRERWERE [SEQ ID 1091] PEPTIDE : KEDEEEKQKYQYQREKKEQKEVQPGRERW [SEQ ID 1092] PEPTIDE : KQKYQYQREKKEQKEVQPGRERWEREEOE [SEQ ID 1093] PEPTIDE : LPSEFEPINLRSHKPEYSNKFGKLFEITP [SEQ ID 1094] PEPTIDE : EEKRHGEWRP [SEQ ID 1095]

PEPTIDE : KEVQPGRERW [SEQ ID 1096]

PEPTIDE : QKEVQPG E W [SEQ ID 1097]

PEPTIDE : EEKRHGEWRPSY [SEQ ID 1098]

PEPTIDE : RHGEWRPSYEKQ [SEQ ID 1099]

PEPTIDE : KEVQPGRERWERE [SEQ ID 1100]

PEPTIDE : RHGEWRPSYEKQE [SEQ ID 1101]

PEPTIDE : QKEVQPGRERWERE [SEQ ID 1102]

PEPTIDE : KKSLPSEFEPINLRSHKP [SEQ ID 1103]

PEPTIDE : EWRGSQRREDPEERARLRHR [SEQ ID 1104]

PEPTIDE : SSKKSLPSEFEPINLRSHKP [SEQ ID 1105]

PEPTIDE : KPEYSNKFGKLFEITPEKKYP [SEQ ID 1106]

PEPTIDE ; SSSKKSLPSF.FFPINLRSHKP [SEQ ID 1107]

PEPTIDE : HKPEYSNKFGKLFEITPEKKYP [SEQ ID 1108]

PEPTIDE I AKSSSKKSLPSEFEPI LRSHKP [SEQ ID 1109]

PEPTIDE : INLRSHKPEYSNKFGKLFEITPEKKYP (SEQ ID 1110]

PEPTIDE : AKSSSKKSLPSEFEPINLRSHKPEYSNKF [SEQ ID 1111] PEPTIDE : RRNPFLFKSNKFLTLFE [SEQ ID 1112]

PEPTIDE : PINLRSHKPEYSNKFGKLFEITPEKKYPQ [SEQ ID 1113] PEPTIDE : KPEYSNKFGKLFEITPEKKYPQLQ [SEQ ID 1114]

PEPTIDE : HKPEYSNKFGKLFEITPEKKYPQLQ (SEQ ID 1115]

PEPTIDE : SHKPEYSNKF6KLFEITPEKKYPQLQ [SEQ ID 1116]

PEPTIDE : FEP!NLRSHKPEYSNKFGKLFEITPEKK [SEQ ID 1117]

PEPTIDE : ASINRPIVFFTVCLFLLCNGSLA [SEQ ID 1118]

PEPTIDE : FLLAGNKRNPQ [SEQ ID 1119]

PEPTIDE : FLLAGNKRN [SEQ ID 1120]

PEPTIDE : VLDLAIPVNRPGQLQSFLLSGNQNQQNYLSGFS [SEQ I D 1121] PEPTIDE : QSFLLSGNQNQQNYLSG [SEQ ID 1122]

PEPTIDE : RLSSV [SEQ ID 1123]

PEPTIDE : QKEFLLAGNNNR (also in P14614) [SEQ ID 1124]

PEPTIDE : LLRPAFAQQQEQAQQQEQA [SEQ ID 1125]

PEPTIDE : VKNGLKLLRPAF [SEQ ID 1126]

PEPTIDE : F1.1.AGNNNRE (SEQ ID 1127]

PEPTIDE : GLKLLRPAFAQQQE [SEQ ID 1128]

PEPTIDE : LKLLRPAFAQQQE [SEQ ID 1129]

PEPTIDE : LLRPAFAQQQE [SEQ ID 1130]

PEPTIDE : QKEFLLAGNNNR (also in P14323) [SEQ ID 1131]

PEPTIDE : LRGFSKN [SEQ ID 1132]

PEPTIDE ; SRGPIYSNEFGK [SEQ ID 1133]

PEPTIDE : N5FNLER [SEQ ID 1134]

PEPTIDE : VLDLAIPVNR [SEQ ID 1135]

PEPTI DE : DDNEELR [SEQ ID 1136]

PEPTIDE : LSSGDVFVIPAGHPVAVK (SEQ ID 1137]

PEPTIDE : EDDEEEEQGEEEINK [SEQ ID 1138]

PEPTIDE : NILEASFNTDYEEIEKVLLEEHEKETQHR [SEQ ID 1139] PEPTIDE : NILEASFNTDYEEIEKVLLEEHEK [SEQ ID 1140]

PEPTIDE : NILEASFNTDYEEIEK {SEQ ID 1141)

PEPTIDE : RQQSQEENVIVK [SEQ ID 1142]

PEPTIDE : QQSQEENVIVK [SEQ ID 1143]

PEPTIDE : LSRGQIEELSK [SEQ ID 1144]

PEPTIDE : GQIEELSK [SEQ ID 1145]

PEPTIDE : VLLEEHEK [SEQ ID 1146]

PEPTIDE : SKPHTIFLPQHTDADYILVVLSG [SEQ ID 1147]

PEPTIDE : PHTIFLPQHTDADYILVVLSG [SEQ ID 1148]

PEPTIDE : SNKFQTLFENENGHIR [SEQ ID 1149]

PEPTIDE : SKIFENLQNYR [SEQ ID 1150]

PEPTIDE : IFENLQNYR [SEQ ID 1151]

PEPTIDE : ILENQKQSHFADAQPQQR [SEQ ID 1152]

PEPTIDE PGQLQSFLLSGNQNQQNYLSGFSK [SEQ ID 1153]

PEPTIDE : FFELTPEKNQQLQDLDLFVNSVDLK [SEQ ID 1154]

PEPTIDE : QLEELS [SEQ ID 1155]

PEPTIDE : QEEDEDEDEER [SEQ ID 1156]

PEPTIDE : YQHQQGGKQEQENEGNNIFSGFK [SEQ ID 1157]

PEPTIDE : GDTIKLPAGTTSYLVNQDDEEDLR [SEQ ID 1158]

PEPTIDE : RQQGEETDAIVK [SEQ ID 1159]

PEPTIDE : VLLEEQEKDRK [SEQ ID 1160]

PEPTIDE : NILEASYNTR [SEQ ID 1161)

PEPTIDE : FEAFDLAK [SEQ ID 1162]

PEPTIDE : EQIEELKK [SEQ ID 1163]

PEPTIDE : EQiEELK [SEQ ID 1164]

PEPTIDE : NKNQYLR [SEQ ID 1165]

PEPTI DE : LSPGDWIIPAGHPVAITASSNLNLLGFGINAENNER [SEQ ID 1166]

PEPTIDE ; PSYEKQEDEEEKQK [SEQ ID 1167]

PEPTIDE : EEDEEEGQR [SEQ ID 1168]

PEPTIDE : TLFLPQYTDADFU WLSGK [SEQ ID 1169]

PEPTIDE: LVDLVIPVNGPGKFEAFDLAK [SEQ ID 1170]

PEPTIDE: KNPQLQDLDIFVNYVEIK [SEQ ID 1171]

PEPTIDE: GYVGLTFPGCPATHQQQFQLFEQR [SEQ ID 1172]

PEPTIDE: RGPQQYAEWQINEK [SEQ ID 1173]

PEPTIDE : DEHQKIHQFR [SEQ ID 1174]

PEPTIDE : FRDEHQK [SEQ ID 1175]

PEPTIDE : FPILNLIQ SATR [SEQ ID 1176]

PEPTIDE : TNANAFVSHLAGK [SEQ ID 1177]

PEPTIDE : ALPVDWANAYR [SEQ ID 1178]

PEPTIDE : YVYDVNNNANQLEPRQKEFL [SEQ ID 1179]

PEPTIDE : VYVYDVNNNANQLEPRQKfcFL [SEQ ID 1180]

PEPTIDE : ADSYIMPR [SEQ ID 1181]

PEPTIDE : KPTLTQQQEQAQAQDQ [SEQ ID 1182]

PEPTIDE : QAQAQDQYQQVQY [SEQ ID 1183]

PEPTIDE : QAQDQYQQVQY [SEQ ID 1184]

PEPTIDE : LQAFEPLR [SEQ ID 1185]

PEPTIDE : SRVQWSNFGK [SEQ ID 1186]

PEPTIDE : WNVNAHSLVY [SEQ ID 1187]

PEPTIDE : NVNAHSLVY [SEQ ID 1188]

PEPTIDE : IQGRSRVQVVSNFGK [SEQ ID 1189]

PEPTIDE : GKTVFDGVIRPGQL [SEQ ID 1190]

PEPTIDE : FGKTVFDGVLRPGQL [SEQ ID 1191]

PEPTIDE : FQQQYYPGLSNESESETSE [SEQ ID 1192]

PEPTIDE : QQYYPGLSN [SEQ ID 1193}

PEPTIDE : QQQYYPGLSN [SEQ ID 1194]

PEPTIDE : VTNLNTQNFPILSLVQMSAVK [SEQ ID 1195]

PEPTIDE : I TQG A QVV G TVF [SEQ ID 1196] PEPTIDE ; ITQG RAR VQVVN N G TVF G E [SEQ ID 1197]

PEPTIDE : ITQGRARVQVVNNNGKTVFN6 [SEQ ID 1198]

PEPTIDE : RVQVVNNNGKTVF [SEQ, ID 11993

PEPTIDE : RALPNDVLANAYRISREE [SEQ ID 1200)

PEPTIDE ; SIFRALPNDVLANAYR [SEQ ID 1201]

PEPTIDE : SIFRALPNDVLANAY [SEQ ID 1202]

PEPTIDE : SIFRALPNDVLAN [SEQ ID 1203]

PEPTIDE : SSIFRALPNDVLANAYR [SEQ ID 1204]

PEPTIDE : SIFRALPNDVLA AYRISREE [SEQ ID 1205]

PEPTIDE : SIFRALPND [SEQ ID 1206]

PEPTIDE : IYVTDLNNGANQLDPRQRD [SEQ ID 1207]

PEPTIDE : VTNLNSQNFPI L LVQMSAV [SEQ ID 1208]

PEPTIDE : QNIDNPNR [SEQ ID 1209]

PEPTIDE : ADTYNPR [SEQ ID 1210]

PEPTIDE : NiDNP RADTYNPRAGRVTNL [SEQ ID 1211)

PEPTIDE : RVRQNIDNPNRADTYNPRAGRVTNL [SEQ ID 1212]

PEPTIDE : TNPNSMVSHIAG SSIFR [SE ID 1213]

PEPTIDE : HNRGDEFGAFTPLQYK [SEQ ID 1214]

PEPTIDE ; SYQDVYNVAESS [SEQ ID 1215]

PEPTIDE ; ISREEAQR [SEQ ID 1216]

PEPTIDE ; SIFRALPTDVLANAYRISREE [SEQ ID 1217]

PEPTIDE : YRISREEAQRLKHNRGDEF [SEQ ID 1218]

PEPTIDE : YRISREEAQRLKHNRGDE [SEQ ID 1219]

PEPTIDE : F DEHQKIHR [SEQ ID 1220]

PEPTIDE : QGDVIALPAGVAHW [SEQ ID 1221)

PEPTIDE : TVFNGELRR [SEQ ID 1222]

PEPTIDE : TVFNGELR [SEQ ID 1223]

PEPTIDE : QVQVVNNNG TVF [SEQ ID 1224]

PEPTIDE : YIIQGRGITGPTF [SEQ ID 1225]

PEPTIDE : VYIIQGRGITGPTF [SEQ ID 1226)

PEPTIDE ; LQAFEPIRSVR [SEQ ID 1227]

PEPTIDE : GLSLLQPYASLQEQEQGQ QSR [SEQ ID 1228]

PEPTIDE : GEIVRVER [SEQ ID 1229]

PEPTIDE : RGLSLLQPYASLQ [SEQ ID 1230)

PEPTIDE ; RGLSLLQPYASLQEQ [SEQ ID 1231]

PEPTIDE : RGLSLLQPYASLQEQE [SEQ ID 1232]

PEPTIDE ; RGLSLLQPYASLQE [SEQ ID 1233]

PEPTIDE : RNPQAYR [SEQ ID 1234]

PEPTIDE ; FLLAGNKRNPQAY [SEQ ID 1235)

PEPTIDE : EVEEWSQNIF [SEQ ID 1236]

PEPTIDE : LAGNKRNPQAYR [SEQ ID 1237]

PEPTIDE : FLLAGNKRNPQA [SEQ ID 1238]

PEPTIDE : ELGAPDVGHPMSE [SEQ ID 1239]

PEPTIDE : IVQGHARVQWSNLG [SEQ ID 1240]

PEPTIDE : I VQG H A RVQVVS N L [SEQ ID 1241]

PEPTIDE : IVQGHARVQWSN [SEQ ID 1242]

PEPTIDE : NNRGEELGAFTPR [SEQ ID 1243]

PEPTIDE : GEELGAFTPR [SEQ ID 1244]

PEPTIDE : FPILNLVQLSATR [SEQ ID 1245]

PEPTIDE ; 5IEQHSGQNIFSGFN ELLSEALGVNALVAK [SEQ ID 1246]

PEPTIDE : LQGQNDQR [SEQ ID 1247]

PEPTIDE ; SGFNNELLSEALGVNALVAK [SEQ ID 1248]

PEPTIDE ; PAFAQQQEQAQQQEQAQAQY [SEQ ID 1249]

PEPTIDE : VAKRLQGQNDQRGEI [SEQ ID 12S0]

PEPTIDE : ALVAKRLQGQNDQRGEI [SEQ ID 1251]