US20190091282A1 - Peptides for use in promoting transport of glucose - Google Patents

Peptides for use in promoting transport of glucose Download PDF

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US20190091282A1
US20190091282A1 US15/744,403 US201615744403A US2019091282A1 US 20190091282 A1 US20190091282 A1 US 20190091282A1 US 201615744403 A US201615744403 A US 201615744403A US 2019091282 A1 US2019091282 A1 US 2019091282A1
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seq
peptide
sequence
peptides
fragment
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Nora KHALDI
Cyril LOPEZ
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Nuritas Ltd
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Nuritas Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/38—Other non-alcoholic beverages
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Muscle also plays a crucial role in blood glucose level regulation. Indeed, 80% of glucose consumed is absorbed by the skeletal muscle and then transformed into glycogen (a form of energy storage). All this makes the maintenance of healthy skeletal muscle paramount for overall health and wellbeing.
  • muscle health is crucial. Firstly, muscle loss causes immobility and, with an ageing population on the rise, this is becoming a huge problem. Secondly, active individuals want to maintain their muscle mass, remain athletic, competitive and healthy. Finally, low muscle-glucose absorption can cause high blood glucose levels which can lead to severe conditions such as pre-diabetes and, ultimately, diabetes.
  • the pea genome codes for over 70,000 different proteins.
  • the Applicant has identified two of these proteins, each of which contains one or more peptides capable of facilitating glucose transport in mammalian skeletal muscle (hereafter “glucose transport promoting peptide” or “glucose transport promoting fragment”).
  • the Applicant has identified four proteins, each of which contains one or more peptides capable of facilitating glucose transport in mammalian skeletal muscle.
  • Glucose transport promoting fragments of the six identified proteins, and compositions containing a plurality of the glucose transport promoting peptides have been shown to cause a significant increase in cell surface GLUT4 translocation in response to insulin stimulation in-vitro ( FIGS. 1-6 ).
  • the specific plant proteins from which the natural peptides are derived are described herein, for example in SEQUENCE ID NO: 1-6.
  • the specific pea proteins from which the peptides are derived are provided in SEQUENCE ID NO: 1-2, and the specific rice proteins from which the peptides are derived are provided in SEQUENCE ID NO: 3-6. Homologs of these proteins are described in SEQUENCE ID NO: 67-84.
  • the specific peptides initially identified in the pea proteins are shown in SEQUENCE ID NO's: 7-46.
  • the specific peptides initially identified in the rice proteins are shown in SEQUENCE ID NO's: 47-66.
  • the peptides of the invention are primarily useful for causing an increase in glucose uptake in mammalian skeletal muscle, and therefore have utility in improving muscle health generally, but also find utility in treatment or management of metabolic conditions characterised by dysregulated glucose or insulin levels in mammals, for example diabetes and more specifically regulating glucose homeostasis and attenuating insulin resistance.
  • the invention provides a peptide, typically 3 to 50 amino acids in length, and comprising a fragment of a protein selected from SEQUENCE ID NO's: 1 to 6 or 227 to 234, or a homolog thereof, or a variant of the peptide (hereafter “peptide of the invention”).
  • peptide of the invention a protein selected from SEQUENCE ID NO's: 1 to 6 or 227 to 234, or a homolog thereof, or a variant of the peptide (hereafter “peptide of the invention”).
  • the peptide or variant thereof is bioactive.
  • the peptide or variant thereof has glucose transport promoting activity.
  • the peptide comprises a sequence selected from SEQUENCE ID NO: 7-66 and 85-226. In one embodiment, the peptide comprises a sequence selected from SEQUENCE ID NO: 7, 13 and 51.
  • the peptide consists essentially of a sequence selected from SEQUENCE ID NO: 7-66 and 85-226. In one embodiment, the peptide consists essentially of a sequence selected from SEQUENCE ID NO: 7, 13 and 51.
  • the peptide of the invention is glucose transport promoting. In other embodiments, the peptide or variant is anti-inflammatory. In other embodiments, the peptide or variant is antibacterial. In other embodiments, the peptide or variant has cellular growth or proliferation promoting activity.
  • the fragment has between 8 and 23 amino acids. In one embodiment, the fragment has a charge of ⁇ 5 and +3.
  • the c-terminal amino acid is not C, I, K, M, P, T or W.
  • the n-terminal amino acid is not C, D, H, M, P, T, V, W.
  • the c-terminal domain of the fragment does not contain C, M or W.
  • the n-terminal domain of the fragment does not contain C, M, T or W.
  • the fragment or peptide does not contain C.
  • the fragment or peptide does not contain M.
  • the peptide of the invention comprises a fragment selected from SEQUENCE ID NO's: 7-66, or a bioactive variant of the fragment.
  • the peptide of the invention consists of a fragment selected from SEQUENCE ID NO's: 7-66, or a bioactive variant of the fragment.
  • the peptide consists of a sequence selected from SEQUENCE ID NO's: 7-66.
  • the peptide comprises or consists of a sequence selected from SEQUENCE ID NO's: 7-20.
  • the peptide comprises or consists of SEQUENCE ID NO: 7.
  • the invention also provides a peptide of the invention in a modified form (modified peptide).
  • the invention also provides a conjugate comprising a peptide of the invention conjugated to a binding partner.
  • the peptide comprises a bioactive fragment of the protein of SEQUENCE ID NO: 1 or a homolog thereof, or a bioactive variant of the fragment.
  • the bioactive peptide or fragment is glucose transport promoting.
  • the bioactive fragment comprises the sequence LAIPVNR (SEQ ID NO: 235).
  • bioactive fragments include the LAIPVNR motif include SEQ ID NO'S 7, 8, 10, 12 and 14.
  • the peptide of the invention (or bioactive fragment) comprises the sequence SFLLSGNQNQ (SEQ ID NO: 236).
  • bioactive fragments including this motif include SEQ ID NO'S 9, 11, 13, 16, 17, 190, 191, 192 and 204.
  • the invention comprises a sequence of
  • the bioactive fragment comprises the sequence GSLLLPHYN (SEQ ID NO: 237).
  • bioactive fragments including this motif include SEQ ID NO'S 18 and 19.
  • the peptide comprises a bioactive fragment selected from SEQUENCE ID NO'S: 7-20, or a bioactive variant of the fragment.
  • the invention also provides a composition comprising at least 1, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, or preferably at least 10 bioactive peptides of the invention.
  • each comprises a different a bioactive fragment of SEQUENCE ID NO: 1 (for example the fragments of SEQ ID 7-20), or a homolog thereof.
  • the composition comprises a first bioactive peptide comprising a first bioactive fragment selected from SEQUENCE ID NO: 7-20 (or a bioactive variant of the fragment), and a second bioactive peptide comprising a second a bioactive fragment selected from SEQUENCE ID NO: 7-20 (or a bioactive variant of the fragment).
  • the composition comprises substantially all of the fragments of SEQ ID 7-20, or peptides of the invention comprising all of the fragments of SEQ ID 7-20.
  • Homologs of Pea Protein 1 include Vicia fabia, Cicer arietinum and Lens culinaris homologs (SEQ ID NO: 67-69).
  • the peptide comprises a bioactive fragment of the protein of SEQUENCE ID NO: 2, or a homolog thereof, or a bioactive variant of the fragment.
  • the peptide or fragment is glucose transport promoting.
  • the peptide comprises a bioactive fragment selected from SEQUENCE ID NO'S: 21-46, or a bioactive variant of the fragment.
  • the invention also provides a composition comprising at least 1, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, or preferably at least 10 bioactive peptides of the invention.
  • each peptide comprises a different a bioactive fragment of SEQUENCE ID NO: 2 (for example the fragments of SEQ ID 21-46), or a homolog thereof.
  • the composition comprises a first bioactive peptide comprising a bioactive fragment selected from SEQUENCE ID NO 21-46, and a second bioactive peptide comprising a bioactive fragment selected from SEQUENCE ID NO 21-46.
  • the composition comprises substantially all of the fragments of SEQ ID 21-46, or peptides of the invention comprising all of the fragments of SEQ ID 21-46.
  • Homologs of Pea Protein 2 include Pisum abyssinicum, Lathyrus annuus , and Vicia villosa (SEQ ID 70-72).
  • the peptide comprises a bioactive fragment of the protein of SEQUENCE ID NO: 3, or a homolog thereof, or a bioactive variant of the fragment.
  • the peptide or fragment is glucose transport promoting.
  • the peptide comprises a bioactive fragment selected from SEQUENCE ID NO 47, or a bioactive variant of the fragment.
  • the invention also provides a composition comprising at least 1, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, or preferably at least 10 bioactive peptides of the invention.
  • Homologs of Rice Protein 1 include Oryza rufipogon, Oryza officinalis, Hordeum vulgare subsp. vulgare (SEQ ID NO: 73-75).
  • the peptide comprises a bioactive fragment of the protein of SEQUENCE ID NO: 4, or a homolog thereof, or a bioactive variant of the fragment.
  • the fragment or peptide is glucose transport promoting.
  • the peptide comprises a bioactive fragment selected from SEQUENCE ID NO'S: 48-59, or a bioactive variant of the fragment.
  • the invention also provides a composition comprising at least one or more peptides of the invention that comprise different bioactive fragments of SEQUENCE ID NO: 4 or a homolog thereof.
  • the composition comprises a first peptide comprising a bioactive fragment SEQ ID NO: 48-59 and a second peptide comprising a bioactive fragment SEQ ID NO: 48-59.
  • the composition comprises substantially all of the fragments of SEQ ID 48-59, or peptides of the invention comprising all of the fragments of SEQ ID 48-59.
  • Homologs of Rice Protein 2 include Oryza brachyantha , and Zizania latifolia (SEQ ID NO: 76-78).
  • the peptide comprises a bioactive fragment of the protein of SEQUENCE ID NO: 5, or a homolog thereof, or a bioactive variant of the fragment.
  • the fragment or peptide is glucose transport promoting.
  • the peptide comprises a bioactive fragment selected from SEQUENCE ID NO'S: 60-63, or a bioactive variant of the fragment.
  • the invention also provides a composition comprising at least 1, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, or preferably at least 10 bioactive peptides of the invention, each of which comprises a different bioactive fragment of SEQUENCE ID NO: 5 or a homolog thereof.
  • the composition comprises a first bioactive peptide comprising a bioactive fragment selected from SEQUENCE ID NO 60-63, and a second bioactive peptide comprising a bioactive fragment selected from SEQUENCE ID NO 60-63.
  • Homologs of Rice Protein 3 include Oryza sativa Japonica Group and Seed Storage Globulin (SEQ ID 79-81).
  • the peptide comprises a bioactive fragment of the protein of SEQUENCE ID NO: 6 or a homolog thereof, or a bioactive variant of the fragment.
  • the peptide comprises a bioactive fragment selected from SEQUENCE ID NO'S: 64-66, or a bioactive variant of the fragment.
  • the invention also provides a composition comprising at least 1, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, or preferably at least 10 bioactive peptides of the invention, each of which comprises a bioactive fragment of SEQUENCE ID NO: 6 or a homolog thereof.
  • the composition comprises a first bioactive peptide comprising a bioactive fragment selected from SEQUENCE ID NO 64-66, and a second bioactive peptide comprising a bioactive fragment selected from SEQUENCE ID NO 64-66.
  • Homologs of Rice Protein 4 include glutelin ( Oryza sativa Japonica Group), Glutelin precursor ( zizania latifolia ) anmd globulin ( avena sativa ) (SEQ ID NO: 82-84).
  • the invention also provides a composition comprising at least one and preferably a plurality of bioactive (i.e. glucose transport promoting) peptides of the invention, wherein each of the peptides of the invention comprises a bioactive (i.e. glucose transport promoting) fragment of a protein selected from SEQUENCE ID NO: 1 to 6 or a homolog thereof, or a bioactive (i.e. glucose transport promoting) variant or fragment thereof.
  • bioactive i.e. glucose transport promoting
  • the or each bioactive (i.e. glucose transport promoting) peptide of the invention is selected from, or comprises, a bioactive (i.e. glucose transport promoting) fragment selected from, SEQUENCE ID NO: 7-66 and 85-226, or a bioactive (i.e. glucose transport promoting) variant or fragment thereof.
  • the invention also provides a composition comprising at least one and preferably a plurality of peptides of the invention, wherein the or each of the peptides of the invention comprise a bioactive (i.e. glucose transport promoting) fragment of a protein selected from SEQUENCE ID NO: 1-2.
  • the or each peptide of the invention is selected from, or comprises a bioactive (i.e. glucose transport promoting) fragment selected from, SEQUENCE ID NO: 7-46, or a bioactive (i.e. glucose transport promoting) variant of the fragment.
  • the composition includes SEQUENCE ID NO'S 7 and 13, and optionally a plurality of peptides selected from SEQUENCE ID NO'S 8 to 12 and 14 to 46.
  • the invention also provides a composition comprising substantially all of the fragments of SEQ ID NO's 7-46, or peptides comprising the fragments, or bioactive (i.e. glucose transport promoting) variants of the fragments
  • the invention also provides a composition comprising at least one and preferably a plurality of peptides of the invention, wherein the or each of the peptides of the invention comprise a bioactive (i.e. glucose transport promoting) fragment of a protein selected from SEQUENCE ID NO: 3-6.
  • the or each peptide of the invention is selected from, or comprises a bioactive (i.e. glucose transport promoting) fragment selected from, SEQUENCE ID NO: 47-66, or a bioactive (i.e. glucose transport promoting) variant of the fragment.
  • the invention also provides a composition comprising substantially all of the fragments of SEQ ID NO's 47-66, or peptides comprising the fragments, or bioactive (i.e. glucose transport promoting) variants of the fragments.
  • the composition comprises at least two distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least three distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least four distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least five distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least six distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least seven distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least eight distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least nine distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the composition comprises at least ten distinct bioactive (i.e. glucose transport promoting) peptides of the invention.
  • the invention comprises a composition comprising substantially all of fragments SEQUENCE ID NO: 7-66, or peptides containing the fragments, or bioactive (i.e. glucose transport promoting) variants of the fragments, or a mixture of the bioactive (i.e. glucose transport promoting) fragments and variants.
  • the invention also relates to a comestible product comprising a bioactive (i.e. glucose transport promoting) peptide or fragment of the invention.
  • a comestible product comprising a bioactive (i.e. glucose transport promoting) peptide or fragment of the invention.
  • the comestible product is man-made.
  • the invention also relates to a comestible product comprising a composition of peptides or fragments of the invention.
  • a comestible product comprising a composition of peptides or fragments of the invention.
  • the comestible product is man-made.
  • the comestible product is a food product for human or animal or cellular consumption.
  • the man-made comestible product is a nutritional supplement.
  • the comestible product is a sports nutrition product, for example a beverage, snack or supplement.
  • the man-made comestible product is a beverage.
  • the man-made comestible product is a bakery product.
  • the man-made comestible product is a dairy product.
  • the man-made comestible product is a snack product.
  • the man-made comestible product is a baked extruded food product.
  • the man-made comestible product is powdered milk.
  • the man-made comestible product is an infant formula product.
  • the man-made comestible product is a confectionary product.
  • the man-made comestible product is a yoghurt. In one embodiment the man-made comestible product is a yoghurt drink. In one embodiment the man-made comestible product is an ice cream product. In one embodiment the man-made comestible product is a frozen food product. In one embodiment the man-made comestible product is a breakfast cereal. In one embodiment the man-made comestible product is a bread. In one embodiment the man-made comestible product is a flavoured milk drink. In one embodiment the man-made comestible product is a confectionary bar. In one embodiment the man-made comestible product is a tea or tea product. In one embodiment the man-made comestible product is a based extruded snack product.
  • the man-made comestible product is a fried snack product. In one embodiment the man-made comestible product is a nutritional supplement. In one embodiment the man-made comestible product is a sports nutritional product. In one embodiment the man-made comestible product is a baby food product. In one embodiment the man-made comestible product is a specialty food product for immunocompromised individuals. In one embodiment the man-made comestible product is a food for geriatric patients.
  • the invention also relates to a peptide of the invention for use in improving muscle status in a mammal.
  • the invention also relates to a composition of the invention for use in improving muscle status in a mammal.
  • the invention also relates to a peptide of the invention for use in promoting recovery of muscle, typically following exercise.
  • the invention also relates to a composition of the invention for use in promoting recovery of muscle, typically following exercise.
  • the invention also relates to a peptide of the invention for use in maintaining or restoring muscle health (for example lean tissue mass) in a mammal.
  • the invention also relates to a composition of peptides of the invention for use in maintaining or restoring muscle health (for example lean tissue mass) in a mammal.
  • the invention also relates to a peptide of the invention for use in enhancing physical performance.
  • the invention also relates to a composition of the invention for use in enhancing physical performance.
  • the invention also relates to a peptide of the invention for use in preventing or treating a metabolic disorder characterised by dysregulated glucose or insulin levels in a mammal.
  • a metabolic disorder characterised by dysregulated glucose or insulin levels in a mammal.
  • the disorder is diabetes.
  • the invention also relates to a composition of the invention for use in preventing or treating a metabolic disorder characterised by dysregulated glucose or insulin levels in a mammal.
  • a metabolic disorder characterised by dysregulated glucose or insulin levels in a mammal.
  • the disorder is diabetes.
  • the invention also relates to a peptide of the invention for use in improving glycaemic management in a mammal.
  • the invention also relates to a composition of the invention for use in improving glycaemic management in a mammal.
  • the invention also relates to a peptide of the invention for use in one or more of: reducing plasma glucose levels in mammals; regulating glucose homeostasis; and attenuating insulin resistance.
  • the invention also relates to a composition of the invention for use in one or more of:
  • the invention also relates to a peptide of the invention for use in treatment or prevention of a disease or condition characterised by lethargy or low energy levels.
  • the invention also relates to a composition of peptides of the invention for use in treatment or prevention of a disease or condition characterised by lethargy or low energy levels.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a peptide of the invention in combination with a pharmaceutically acceptable carrier.
  • the peptide is a glucose transport promoting peptide.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a composition of peptides of the invention in combination with a pharmaceutically acceptable carrier.
  • the invention also relates to a comestible product, for example a food product comprising a peptide or composition of the invention, for example a dairy or non-dairy product, a solid food or a beverage, a food additive or supplement.
  • a dairy product may be a milk, a cheese, or yoghurt.
  • the food product is a sports nutritional product.
  • the food product may comprise any amount of the composition of the invention, for example from 0.1% to 30% (w/w).
  • 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).
  • the peptides of the present invention are preferably used from about 0.00001% w/w to about 0.5% w/w [0.1 to 5000 ppm], and more preferably from 0.00005 w/w to about 0.05 w/w [0.5 to 500 ppm], and most preferably from about 0.0001 w/w to about 0.01 w/w of the composition [1 to 100 ppm].
  • the peptides of the present invention are preferably used from about 0.0001% w/w to about 0.004% w/w of the composition.
  • a typical daily dosage may be 0.2 g to 100 g. However, when administered as a food for special medicinal purpose, or medical food, the daily dosage may be 50-500 g per day.
  • compositions of the invention for use in food products and food supplements will be broadly in the 0.2-100 g/day range.
  • the daily dosage is 1-10 g/day, ideally about 3-8 g/day.
  • the daily dosage is 10-20 g/day.
  • the daily dosage is 20-30 g/day.
  • the daily dosage is 30-40 g/day.
  • the daily dosage is 10-100 g/day.
  • the daily dosage is about 5 g/day, ideally about 3-8 g/day.
  • the dosage is 2-1000 mg/day/kg body weight.
  • the dosage is 10-500 mg/day/kg body weight.
  • the dosage is 10-100 mg/day/kg body weight.
  • the dosage is 30-70 mg/day/kg body weight.
  • the dosage of peptides of the invention for food supplements may be 0.00001 mg-0.01 mg per day or dose.
  • the food product may be a Food for Specific Medicinal Purposes (FSMP) which is defined as foods that are specifically formulated, processed and intended for the dietary management of diseases, disorders or medical conditions of individuals who are being treated under medical supervision. These foods are intended for the exclusive or partial feeding of people whose nutritional requirements cannot be met by normal foods.
  • FSMP Food for Specific Medicinal Purposes
  • the invention also provides topical composition comprising a peptide of the invention.
  • the topical composition may comprise a plurality of peptides, fragments and/or variants.
  • the topical composition comprises substantially all the peptides.
  • the topical composition comprises substantially all the variants.
  • 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.
  • 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.
  • a medical 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.
  • the device is in direct contact with the keratinous layer such as the skin, thus releasing the peptides of the invention.
  • the topical composition may be incorporated in any suitable form as detailed herein.
  • 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.
  • the device is adapted to release a constant quantity of the composition or the peptides of the invention.
  • 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.
  • the topical composition may further comprise at least one cosmetically or pharmaceutically acceptable excipient.
  • Excipient may be used interchangeably 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.
  • 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.
  • 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.
  • Suitable diluents include, but are not limited to, any diluent disclosed in disclosed in US2014120131 or US2004132667. Examples include ethanol, glycerol and water.
  • 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.
  • 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, carboxymethyl cellulose and polyethylene glycol and any suitable binder disclosed in US2014120131 or US2004132667.
  • 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.
  • 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, betaines, glycosides, maltosides, fatty alcohols, nonoxynols, poloxamers, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, or digitonin. It will be understood that the carrier will be dermatologically acceptable.
  • Preferred carriers contain an emulsion such as oil-in-water, water-in-oil, water-in-oil-in-water and oil-in-water-in-silicone emulsions.
  • Emulsions may further contain an emulsifier and/or an anti-foaming agent.
  • 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.
  • 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.
  • additional ingredients include, but are not limited to, one or more of cleaning agents, conditioning agents, sunscreen, pigment, moisturiser, 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, aloe 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.
  • Any additional ingredients should be suitable for application to the skin without undue toxicity, incompatibility and/or allergic reaction.
  • 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.
  • the additional ingredient may be farnesol ([2E, 6E], ⁇ 3, 7, 11,-trimethyl-2, 6, 10, dodecatrien-1-ol), phytantriol (3, 7, 11, 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, sunscreen 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 US2014120131 or US2004132667.
  • anti-acne actives examples include, resorcinol, salicylic acid, erythromycin, zine, sulfur, benzoyl peroxides.
  • thickening agents are as disclosed in US2014120131 or US2004132667 and include carboxylic acid polymers, crosslinked polyacrylate polymers, polyacrylamide polymers, polysaccharides.
  • conditioning agents are as disclosed in US2014120131 or US2004132667 and include humectants, moisturiser or skin conditioner.
  • structuring agents are as disclosed in US2014120131 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 ⁇ -lactam 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 bupivacaine and those disclosed in US2014120131 or US2004132667.
  • 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.
  • sunscreen actives include any suitable organic or inorganic sunscreen active.
  • Examples include metallic oxides, 2-ethylhexyl-p-methoxycinnamate and those disclosed in US2014120131 or US2004132667.
  • Examples of skin healing agents includes panthenoic acid as disclosed in US2014120131 or US2004132667.
  • 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.
  • flavonoids examples include flavanones, methoxy flavonones, unsubstituted chalcone and mixtures thereof and those disclosed in US2014120131 or US2004132667.
  • enzymes include lipases, proteases, catalase, super oxide-dismutase, amylase, peroxidase, glucuronidase, ceramidases, hyaluronidases.
  • enzyme inhibitors include trypsine inhibitors, Bowmann Birk inhibitors, chymotrypsin inhibitors, botanical extracts, flavonoids, quercetin chalcone and those disclosed in US2014120131 or US2004132667 and mixtures thereof.
  • enzyme activators include coenzyme A, Q10 (ubiquinone), glycyrrhizin, berberine, chrysin and those disclosed in US2014120131 or US2004132667 and mixtures thereof
  • anti-wrinkle or anti atrophy actives include sulfur containing D and L amino acids, particular, N-acyl derivatives such as N-acetyl-L-Cysteine, hydroxyl acids, phytic acid, lipoic acid, lysophosphatidic acid, skin peel agents, vitamin B3, retinoids and those disclosed in US2014120131 or US2004132667 and mixtures thereof.
  • N-acyl derivatives such as N-acetyl-L-Cysteine, hydroxyl acids, phytic acid, lipoic acid, lysophosphatidic acid, skin peel agents, vitamin B3, 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.
  • 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.
  • chelators examples 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.
  • 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 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 ingredient should not unacceptably alter the benefits of the peptides of this invention.
  • the topical composition may be alcohol free.
  • 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).
  • the composition 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.
  • 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.
  • additional active agents examples 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.
  • 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 drugs or pharmacological enhancers available on the market.
  • the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition is left on or not removed from the area of the body.
  • 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.
  • 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, electroporation, 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).
  • 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.
  • Suitable methods include, for example, sonication, extrusion, high pressure/homogenization, microfluidization, detergent dialysis, calcium-induced fusion of small liposome vehicles and ether fusion methods, all of which are well known in the art.
  • 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.
  • 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.
  • 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.
  • a further aspect of the invention relates to a pharmaceutical composition
  • 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.
  • a pharmaceutical carrier excipient or diluent
  • 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, 2nd Edition, (1994), Edited by A Wade and P J Weller.
  • 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).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route 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).
  • binders examples 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.
  • 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.
  • preservatives examples include sodium benzoate, sorbic acid and esters of p hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
  • the peptide or composition of the invention may be adapted for topical, oral, rectal, parenteral, intramuscular, intraperitoneal, intra-arterial, intrabronchial, subcutaneous, intradermal, intravenous, nasal, vaginal, buccal or sublingual routes of administration.
  • parenteral intramuscular, intraperitoneal, intra-arterial, intrabronchial, subcutaneous, intradermal, intravenous, nasal, vaginal, buccal or sublingual routes of administration.
  • these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.
  • Other forms of administration comprise solutions or emulsions which may be injected intravenously, intra-arterial, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions.
  • compositions of the present invention may also be in form of suppositories, vaginal rings, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • the composition of the invention may be formulated for topical delivery.
  • 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.
  • 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 iluem, 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 EP1072600.2 and EP13171757.1.
  • An alternative means of transdermal administration is by use of a skin patch.
  • 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.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and 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.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • one or more doses of 10 to 300 mg/day or more preferably, 10 to 150 mg/day will be administered to the patient for the treatment of an inflammatory disorder.
  • 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 anti-inflammatory drugs or pharmacological enhancers available on the market.
  • the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.
  • the peptide of the invention may be administered in the form of a conjugate comprising the peptide, and may optionally include a linker, and a partner molecule, for example a protein such as an antibody molecule intended to increase the half-life of the conjugate in-vivo.
  • the peptide may be modified to substitute one or more amino acids with amino acids employed to attach partner molecules.
  • an amino acid may be substituted with a lysine residue for the purpose of conjugating a partner molecule such as a PEG molecule.
  • 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.
  • the term “comprising” is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps.
  • 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.
  • treatment 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).
  • intervention e.g. the administration of an agent to a subject
  • 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.
  • the term is used synonymously with the term “therapy”.
  • treatment 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.
  • intervention e.g. the administration of an agent to a subject
  • treatment is used synonymously with the term “prophylaxis”.
  • 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.
  • human or animal should be understood to include humans, mammals and other non-mammalian animals such as fish.
  • the human may be an infant, toddler, child, adolescent, adult, or elderly human.
  • the human is an elderly person, for example aged 55 or more.
  • the human is an elderly person experiencing deterioration of lean tissue mass.
  • the human is a sportsperson.
  • the human is pregnant woman.
  • the human is suffering from lethargy or perceived lack of energy.
  • peptide refers to a polymer composed of 5 to 50 amino acid monomers typically 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.
  • 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, Ill. (1984), in M. Bodanzsky and A.
  • 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.
  • side chain modifications include modification of amino groups, such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH 4 ; amidation with methylacetimidate; acetylation with acetic anhydride; carbamylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulfonic acid (TNBS); alkylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxa-5′-phosphate followed by reduction with NABH 4 .
  • modification of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH 4 ; amidation with methylacetimidate; acetylation with acetic anhydride; carbamylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6, trinitrobenzene sulfonic acid (TNBS); alkylation
  • 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 may be modified by carbodiimide activation via o-acylisourea formation followed by subsequent derivatization, for example, to a corresponding amide.
  • Sulfhydryl groups may be modified by methods, such as carboxymethylation with iodoacetic acid or iodoacetamide; performic 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, phenylmercury 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 tetranitromethane 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.
  • Modified peptide In an embodiment of the invention the peptide is a modified peptide.
  • the term modified peptide is used interchangeably with the term derivative of the peptide.
  • the modified peptide includes a peptide which has been substituted with one or more groups as defined herein.
  • the modification may be any modified that provides the peptides and or the composition of the invention with an increased ability to penetrate a cell.
  • the modification may be any modification that increases the half-life of the composition or peptides of the invention.
  • 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.
  • 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.
  • the peptide is R 1 —X—R 2 .
  • R 1 and/or R 2 groups respectively bound to the amino-terminal (N-terminal) and carboxyl-terminal (C-terminal) of the peptide sequence.
  • the peptide is R 1 —X.
  • the peptide is X—R 2 .
  • R 1 is H, C 1-4 alkyl, acetyl, benzoyl or trifluoroacetyl
  • X is the peptide of the invention
  • R 2 is OH or NH 2 .
  • R 1 is 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, substituted or unsubstituted aralkyl, Tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc) and R 5 —CO—, wherein R 5 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 heteroarylalky
  • R 2 is —NR 3 R 4 , —OR 3 or —SR 3 wherein R 3 and R 4 are independently selected from the group formed by H, substituted or unsubstituted C 1 -C 24 alkyl, substituted or unsubstituted C 2 -C 24 alkenyl, Tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), substituted or unsubstituted C 2 -C 24 alkynyl, substituted or unsubstituted C 3 -C 24 cycloalkyl, substituted or unsubstituted C 5 -C 24 cycloalkenyl, substituted or unsubstituted C 8 -C 24 cycloalkynyl, substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted C 7 -C 24 aralkyl, substituted or unsubstituted heterocycly
  • R 3 and R 4 can be bound by a saturated or unsaturated carbon-Carbon bond, forming a cycle with the nitrogen atom.
  • R 2 is —NR 3 R 4 or —OR 3 , wherein R 3 and R 4 are independently selected from the group formed by H, substituted or unsubstituted C 1 -C 24 alkyl, substituted or unsubstituted C 2 -C 24 alkenyl, substituted or unsubstituted C 2 -C 24 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 6 -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.
  • R 3 and R 4 are selected from the group formed by H, methyl, ethyl, hexyl, dodecyl, or hexadecyl. Even more preferably R 3 is H and R 4 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 .
  • R 1 is selected from the group formed by H, acetyl, lauroyl, myristoyl or palmitoyl
  • R 2 is —NR 3 R 4 or —OR 3 wherein R 3 and R 4 are independently selected from H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is —OH or —NH 2 . More preferably, R 1 is acetyl or palmitoyl and R 2 is —NH 2 .
  • the acyl group is bound to the N-terminal end of at least one amino acid of the peptide.
  • 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.
  • the peptide further comprises a modified C-terminus, 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.
  • Conjugate In one embodiment of the invention the peptide is conjugated, linked or fused to a binding partner, for example one or more polyethylene glycol polymers or other compounds, such as molecular weight increasing compounds or lipophilic groups.
  • 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 water-soluble(amphiphilic or hydrophilic) polymer moiety, homo or co-polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG) and polyoxyethylene glycerol (POG), polyamino acids such as poly-lysine, poly-glutamic acid, poly-aspartic acid, particular those of L conformation, pharmacologically inactive proteins such as albumin, gelatin, a fatty acid, olysaccharide, a lipid amino acid and dextran.
  • PEG any water-soluble(amphiphilic or hydrophilic) polymer moiety
  • mPEG monomethyl-substituted polymer of PEG
  • POG polyoxyethylene glycerol
  • polyamino acids such as poly-lysine, poly-glutamic acid, poly-aspartic acid, particular those of L conformation
  • pharmacologically inactive proteins such as albumin
  • the polymer moiety may be straight chained or branched and it may have a molecular weight of 500 to 40000 Da, 5000 to 10000 Da, 10000 to 5000, Da.
  • the compound (binding partner) may be any suitable cell penetrating compound, such as tat peptide, penetratin, pep-1.
  • the compound (binding partner) may be an antibody molecule.
  • the compound (binding partner) 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 cycloalkane or heterocycloalkane.
  • the peptide may be modified at the N-terminal, C-terminal or both.
  • the polymer or compound (binding partner) 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 (binding partner) may be conjugated to the side chain of any suitable residue.
  • the polymer or compound (binding partner) 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 (binding partner) 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 conjugate.
  • bioactive (i.e. glucose transport promoting) peptide means a peptide that includes (a) a bioactive (i.e. glucose transport promoting) 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 bioactive (i.e. glucose transport promoting) variant of the fragment of a plant protein, for example a bioactive (i.e. glucose transport promoting) fragment of a homolog of the plant protein.
  • the peptides or fragments of the invention may be isolated from plant protein 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.
  • Bioactive as applied to a peptide or fragment means having a biological activity when administered to a mammal.
  • the biological activity may be a health promoting activity.
  • Examples of biological activities include glucose transport promoting, anti-bacterial, anti-inflammatory, or cellular growth or proliferation promoting.
  • bioactive means glucose transport promoting.
  • 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%).
  • Anti-inflammatory as applied to a peptide or fragment means a peptide or fragment that is capable of significantly reducing the secretion of TNF ⁇ by LPS-stimulated J774.2 macrophages (compared with untreated LPS-stimulated J774.2 macrophages) when the macrophages are treated with 100 ⁇ M of the peptide or fragment.
  • J774.2 macrophages were treated with 100 ⁇ M of synthetic peptide for 24 hours and then stimulated with (A) LPS (10 ng/ml) for five hours or (B) LPS (10 ng/ml) for 5 hours followed by ATP (5 mM) for one hour. Supernatant was collected and levels of TNF ⁇ were determined by ELISA.
  • Cellular growth or proliferation promoting as applied to a peptide or fragment means a peptide or fragment that is capable of increasing elastin production or cellular proliferation of human skin treated with a 20 ⁇ M solution of peptide 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 BioEstdic International for 5 days. Test items are applied twice per day with 5 ⁇ L 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.
  • each skin explant in the maintenance medium is delipidated with 5 ⁇ L 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% CO2 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 filaggrin is realized by the laboratory Intertek.
  • elastin (rabbit monoclonal antibody, clone P15502, LSBio) is performed using an immunoperoxidase technique two layers (ABC kit, Vector Laboratories) and revealed by AEC (3-amino-9-ethylcarbazole).
  • the immunohistochemical staining intensity in the elastic fibers is evaluated using a semi-quantitative histological score.
  • Epithelial proliferation was analyzed by immunohistochemistry using anti-Ki67 antibody.
  • Immunodetection was performed using an indirect immunoperoxidase technique three layers, amplified (DAKO kit) and revealed by AEC (3-Amino-9-ethylcarbazole).
  • Counting the number of labeled cells is performed and provides the total number of basal cells to calculate the % of labeled cells.
  • the specific staining of filaggrin is performed with an immunoperoxidase staining (ABC kit, Fisher).
  • the intensity of immunohistochemical marker in the epidermis is evaluated relative to the negative control of the solvent (Water or DMSO 0.3%).
  • “Enriched in peptides having a molecular weight of less than 10 KD” as applied to a composition of the invention means that the dry weight % of peptides in the composition having a molecular weight of less than 10 KD is greater than the dry weight % of polypeptide/protein in the composition having a molecular weight of 10 KD or greater.
  • 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%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence homology with the reference protein.
  • homologs of pea protein P13918 include:
  • a “variant” of a bioactive (i.e. glucose transport promoting) fragment shall be taken to mean a fragment having an amino acid sequence that is substantially identical to the reference bioactive (i.e. glucose transport promoting) fragment, and which has the relevant bioactivity (i.e. glucose transport promoting activity) as defined above.
  • the term should be taken to include fragments that are altered in respect of one or more amino acid residues.
  • such alterations involve the insertion, addition, deletion and/or substitution of 5 or fewer amino acids, more preferably of 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.
  • one or more L-amino acids are replaced with D-amino acids.
  • the variant will have at least 70% amino acid sequence homology, preferably at least 80% sequence homology, more preferably at least 90% sequence homology, and ideally at least 95%, 96%, 97%, 98% or 99% sequence homology with the reference glucose transport promoting fragment.
  • 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 variant (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.
  • 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.
  • Variants of SEQUENCE ID NO: 7 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:
  • ILELAVPVNRPGQL (SEQ ID 102) ILELAIPVNKPGQL; (SEQ ID 103) VLELAVPVNKPGQL; (SEQ ID 104) ILELAIPVNRPGEL; (SEQ ID 105) ILDLAIPVNKPGEL; (SEQ ID 106) VLDLAVPVEKPGQL; (SEQ ID 107) VLDLAVPVERPGEL; (SEQ ID 108) VLELAIPVERPGEL.
  • KLDLAIIVNRPGQL KLDLAIIVNRPGQL; (SEQ ID 110) VLDLAIPVNRPGQK; (SEQ ID 111) VLDLAIPVNRPGQL; (SEQ ID 112) VLDLAIPVNRPGQL;; (SEQ ID 113) VLDLAIPVNRPCQL; (SEQ ID 114) VLDLWIPVNRPGQL; (SEQ ID 115) VLDLAIPVNRPGQL; (SEQ ID 116) VLYLAIPVNRPGQL.
  • VLDLYIPVGRPGQL VLDLYIPVGRPGQL
  • VKDLAIPWNRPGQL VKDLAIPWNRPGQL
  • VLDLAIPVNRPCCL VLDLAGGVNRPGQL
  • SEQ ID 121 VLDLAIPKNEPGQL
  • SEQ ID 122 PLDLAIPVNDPGQL
  • SEQ ID 123 VLDLAIPVNRPIQL
  • SEQ ID 124 VLDHAIPVNRPGQL
  • VLDLAIPVNRPGGG VLDLHIPGNEPGQL
  • SEQ ID 127 VYKLAIPVNEPGQL
  • SEQ ID 128) VLDLAIPVNRPYPG
  • SEQ ID 129 VLDYAIPKNDPGQL
  • SEQ ID 130 VLDLAIPVNRPGQL
  • SEQ ID 132) VLDLAIGVNRGPQL
  • VLDLAIPVNRPGFQL VLDLAIPVNRPGFQL
  • VLDLADIPVNRPGQL VLDLADIPVNRPGQL
  • VLDLAIPVGNRPGQL VLDLAIPVGNRPGQL
  • VLQQDLAIPVNRPGQL VLDLAIPVNRGPGQKL
  • SEQ ID 138 VLDGLPLAIPVNRPGQL
  • SEQ ID 139 VLDLAIPVNRPGQLLL
  • Variants of SEQUENCE ID NO: 8 include SEQ ID 7 (three deletions), SEQ ID 14 (one amino acid deletion), and SEQ ID 15 (one addition).
  • Variants of SEQUENCE ID NO: 9 include SEQ ID 13 (one addition) and SEQ ID 11 (three amino acid additions).
  • Variants of SEQUENCE ID NO: 10 include SEQ ID 158 and 161.
  • Variants of SEQUENCE ID NO: 11 include SEQ ID 9 and SEQ ID 13.
  • Variants of SEQUENCE ID NO: 12 include SEQ ID 8 and 16.
  • Variants of SEQUENCE ID NO: 13 include SEQ ID 9 and 11.
  • Variants of SEQUENCE ID NO: 14 include SEQ ID 10 and 15.
  • Variants of SEQUENCE ID NO: 15 include SEQ ID 7, 8, 12 and 14.
  • Variants of SEQUENCE ID NO: 16 include SEQ ID 12.
  • Variants of SEQUENCE ID NO: 17 include SEQ ID 12 and 13.
  • Variants of SEQUENCE ID NO: 18 include SEQ ID 19.
  • variant should also be taken to include fragments of peptides of the invention.
  • the fragment has between 8 and 23 contiguous amino acids in length.
  • the fragment has a charge of ⁇ 5 to +3.
  • the fragment comprises a c-terminal amino acid that is not C, I, K, M, P, T or W.
  • the fragment has an n-terminal amino acid that typically is not C, D, H, M, P, T, V, W.
  • the charge of a peptide, fragment or region is determined using the method of Cameselle, J. C., Ribeiro, J. M., and Sillero, 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.
  • a fragment of a peptide of the invention” or “peptide fragment” may have at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 amino acids and typically has a bioactivity, for example anti-inflammatory activity, anti-ageing activity, glucose transport promoting activity, or anti-bacterial activity.
  • the fragment consists of at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the reference sequence. Examples of fragments of the invention are provided below:
  • VLDLAIPVNRPGQ VLDLAIPVNRPGQ; (SEQ ID 150) VLDLAIPVNRPG; (SEQ ID 151) VLDLAIPVNRP; (SEQ ID 152) LDLAIPVNRPGQL; (SEQ ID 153) DLAIPVNRPGQL; (SEQ ID 154) LAIPVNRPGQL; (SEQ ID 155) LDLAIPVNRPGQ; (SEQ ID 156) DLAIPVNRPG; (SEQ ID 157) LAIPVNRP; (SEQ ID 158) VLDLAIPVN; (SEQ ID 159) AIPVNRPGQL; (SEQ ID 160) VNRPGQL; (SEQ ID 161) VLDLAIPV, and (SEQ ID 10) VLDLAIPVNR.
  • “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.
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route 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).
  • binders examples 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.
  • 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.
  • preservatives examples include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
  • the peptide or composition of the invention may be adapted for topical, oral, rectal, parenteral, intramuscular, intraperitoneal, intra-arterial, intrabronchial, subcutaneous, intradermal, intravenous, nasal, vaginal, buccal or sublingual routes of administration.
  • parenteral intramuscular, intraperitoneal, intra-arterial, intrabronchial, subcutaneous, intradermal, intravenous, nasal, vaginal, buccal or sublingual routes of administration.
  • these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.
  • Other forms of administration comprise solutions or emulsions which may be injected intravenously, intra-arterial, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions.
  • compositions of the present invention may also be in form of suppositories, vaginal rings, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • the composition of the invention may be formulated for topical delivery.
  • 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.
  • 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 iluem, 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 EP1072600.2 and EP13171757.1.
  • An alternative means of transdermal administration is by use of a skin patch.
  • 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.
  • a person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation.
  • a physician will determine the actual dosage which will be most suitable for an individual patient and 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.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the agent may optionally be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • a dose of from 0.01 to 30 mg/kg body weight such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • 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 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 glucose transport promoting drugs or pharmacological enhancers available on the market.
  • the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.
  • the peptide of the invention may be administered in the form of a conjugate comprising the peptide, and may optionally include a linker, and a partner molecule, for example a protein such as an antibody molecule intended to increase the half-life of the conjugate in-vivo.
  • the peptide may be modified to substitute one or more amino acids with amino acids employed to attach partner molecules.
  • an amino acid may be substituted with a lysine residue for the purpose of conjugating a partner molecule such as a PEG molecule.
  • Man-made as applied to comestible products should be understood to mean made by the hand of a human and not existing in nature.
  • “Improving muscle status” means improving the muscle health, for example promoting skeletal muscle protein synthesis, skeletal glucose absorbtion, 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 absorbtion of glucose in skeletal muscle compared with untreated skeletal muscel.
  • 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.
  • 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 from 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.
  • Methodabolic disorder characterised by dysregulated glucose or insulin levels in a mammal should be understood to include pre-diabetes, diabetes; Type-1 diabetes; Type-2 diabetes; metabolic syndrome; obesity; diabetic dyslipidemia; hyperlipidemia; hypertension; hypertriglyceridemia; hyperfattyacidemia; hypercholerterolemia; hyperinsulinemia, MODY, and HNF1A-MODY.
  • “Improving glycaemic management” should be understood to mean one or more of lowering plasma blood glucose levels, especially post-prandial blood glucose levels, treating or preventing hyperglycaemia, increasing post prandial insulin secretion, regulating glucose homeostasis, and reducing or attenuating insulin resistance.
  • FIG. 1A The effect of synthetic peptide SEQ ID 51 (Rice) on glucose uptake in skeletal muscle cells.
  • FIG. 1B The effect of synthetic peptides—SEQ ID 13 (Pea) on glucose uptake in skeletal muscle cells.
  • FIG. 2 The effect of synthetic peptide SEQ ID 66 (Rice) on glucose uptake in skeletal muscle cells.
  • FIG. 3 The effect of synthetic peptide SEQ ID 7 (Rice) on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells.
  • FIG. 4 The effect of peptide composition E_1_BE on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells.
  • FIG. 5 The effect of peptide composition I_2_BE on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells.
  • 2-DG 2-deoxyglucose
  • Human skeletal myoblasts (Sigma 150-05a) 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.
  • 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 ⁇ l of Krebs-Ringer-Phosphate-HEPES (KRPH) and incubated for 1 h. 3. The cells were then stimulated with 100 nM insulin for 30 minutes or 5 ⁇ g/ml, 0.5 ⁇ g/ml or 0.05 ⁇ g/ml synthetic peptide for 3h respectively.
  • PBS Phosphate Buffered Saline
  • KRPH Krebs-Ringer-Phosphate-HEPES
  • 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.
  • 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.
  • GLUT4 insulin-responsive glucose transport protein
  • SP2 [SEQ ID 7] is a glucose transport promoting fragment of Pea Protein P13918, whereas peptides SP1 and SP3-SP6 are comparative peptides.
  • compositions of peptides were tested for skeletal muscle glucose transport activity in an in-vitro test:
  • I_2_BE (comprises peptides of SEQ ID NO: 7 and 10)
  • E_1_BE (comprises peptides of SEQ ID NO: 48, 49, 50, 51, 54, 58, 60, 61, 62, 63)
  • L6-GLUT4myc cells were grown in 10% FBS and 2 ⁇ g/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 30 mins, or 200, 20, 2.0 and 0.2 ⁇ M of SP, and 2, 1, 0.5 and 0.25 mg/ml of peptide 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.
  • the quantity of myc-tagged GLUT4 at the cell surface was measured by antibody-Coupled colorimetric assay. Briefly, after incubation with either insulin for 30 mins or synthetic peptide or peptide 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.
  • PFA paraformaldehyde
  • OPD o-phenylenediamine dihydrochloride
  • DMSO Dimethyl sulfoxide
  • Peptide compositions were prepared by adjusting the pH to between 6-7 using 1 M NaOH or HCL and subsequently sterile filtered.
  • Peptide composition E_1_BE tended to increase GLUT4 translocation at a concentration ranging from 0.25-0.5 mg/ml, however 1 and 2 mg/ml induced progressive cell death. Furthermore, there was a trend for composition I_2_BE to increase GLUT4 translocation in a dose-dependent manner ( FIGS. 4-6 ).
  • I_2_BE or E_1_BE is administered as a solution or suspension in Purified Water.
  • test item formulations at 10 mg/ml in Purified Water are stable for 10 hours at +2-+8° C. protected from light. Therefore test item formulations are kept at +2-+8° C. protected from light and used within 10 hours after preparation. Aspect of formulations and maximal duration of storage are detailed below.
  • mice BKS.Cg-Dock7m+/+Leprdb/J (db/db diabetic mice) (souche JAXTM Mice strain).
  • Choice of species The mouse was chosen because of its acceptance as a predictor of pharmacological effects of drugs in man and the recognition by regulatory authorities that this species is suitable for pharmacodynamic studies.
  • Allocation of treatment to each animal is randomly determined before the start of the study. Homogeneity of groups will be validated on the criterion of body weight and glycaemia measured on the day of randomisation.
  • the number of animals per group is the minimum number enabling an accurate assessment of the pharmacokinetics profile.
  • Blood glucose level is measured weekly from D1 up to D29, 90 ⁇ 30 minutes after the daily treatment.
  • a drop of blood is collected from the tail vein of non fasted db/db mice and is put on the extremity of a glucose strip (Nova Biomedical) placed into the Glucose Meter (Nova Biomedical).
  • the OGTT is performed.
  • animals are dosed by the oral route with 10 mL/kg of a glucose solution at 0.2 g/mL (2 g/kg) in Purified Water.
  • blood glucose level are measured following the same procedure described above, at times 15, 30, 60, 90 and 120 minutes after the glucose overload.
  • I_2_BE and E_1_BE on body weight and glycaemia are compared with those of the vehicle and the delta corresponding to the evolution of blood sugar in each group is calculated from D1 to D15.
  • Evolution of blood glucose from D ⁇ 5 to D1 and therefor prior to treatment shows that progression of the disease is the same in all three groups. Strong trends of activity were observed for both peptide compositions compare to control between D1 and D15 showing that both peptide compositions are able to control the evolution of blood sugar in diabetic animals.
  • I_2_BE and E_1_BE are compared with those of the vehicle using an analysis of variance for repeated measurements with a Dunnett's test in case of significance (P ⁇ 0.05).
  • Biochemical results plasma glucose, HbAlc and insulin
  • the effects of I_2_BE and E_1_BE on biochemical parameters are compared with those of the vehicle using an analysis of variance with a Dunnett's test in case of significance (P ⁇ 0.05).

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