Peptide for use in glucose promotive transport

Abstract

To provide a natural and edible glucose metabolism enhancer, capable of overcoming at least one problem in above-mentioned problems.SOLUTION: There is described a composition including: a natural glucose transport promotive peptide which includes a glucose transport promotive fragment of a protein selected from sequence number 1 to 6, and multiple glucose transport promotive peptides. There is also disclosed use of peptide and composition in improvement of a muscle state in mammalian, especially, promotion of recovery of muscles after taking exercise or enhancement of body performance.SELECTED DRAWING: Figure 1A

Description

[Background technology]

[0001] Nearly 38% of the human body is made up of skeletal muscle. The basic function of this type of muscle is to generate force and enable movement and mobility. It is central to global protein metabolism and the primary reservoir of amino acids (Wolfe RR 2006). Muscle also plays a vital role in regulating blood sugar levels. In fact, 80% of the glucose consumed is absorbed by skeletal muscle and then converted into glycogen (a form of energy storage). All of this makes maintaining healthy skeletal muscle optimal for overall health and well-being.

[0002] Muscle health is important for many reasons. First, muscle loss leads to immobility, which is becoming a greater problem as the aging population increases. Second, active individuals want to maintain their muscle mass to remain fit, competitive, and healthy. Finally, low muscle glucose uptake can cause high blood sugar levels, which can lead to serious conditions such as prediabetes and ultimately diabetes.

[0003] Currently, there are various approaches to improving muscle health or muscle glucose absorption. The former is commonly managed using protein shakes rich in branched-chain amino acids, but these are poorly understood and their effectiveness is controversial. Synthetic insulin is used for muscle glucose absorption. However, insulin retains many functions that affect the rest of the body, causing side effects and insulin resistance.

[0004] Finding alternatives that help restore and maintain muscle and allow glucose to enter the muscle without targeting the insulin receptor is becoming essential for the billions of people suffering from muscle loss and diabetes. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US Patent Application Publication No. 2014120131 [Patent Document 2] US Patent Application Publication No. 2004132667 [Patent Document 3] U.S. Patent No. 4,186,183 [Patent Document 4] U.S. Patent No. 4,217,344 [Patent Document 5] U.S. Patent No. 4,235,871 [Patent Document 6] U.S. Patent No. 4,261,975 [Patent Document 7] U.S. Patent No. 4,485,054 [Patent Document 8] U.S. Patent No. 4,501,728 [Patent Document 9] U.S. Patent No. 4,774,085 [Patent Document 10] U.S. Patent No. 4,837,028 [Patent Document 11] U.S. Patent No. 4,946,787 [Patent Document 12] PCT Publication Number International Publication No. 91 / 17424 Pamphlet [Patent Document 13] European Patent No. 2050437 [Patent Document 14] International Publication No. 2005023290 Brochure [Patent Document 15] US Patent Application Publication No. 2010098660 [Patent Document 16] US Patent Application Publication No. 20070053845 [Patent Document 17] European Patent No. 1072600.2 [Patent Document 18] European Patent No. 13171757.1 [License 19] U.S. Patent and Trademark Office Publication No. 2014120141 [Non-licensed literature]

[0006] [Non-licensed Document 1] Szoka et al, Ann. Rev. Biophys. Bioeng. 9:467(1980) [Non-licensed Document 2] Deamer & Bangham, Biochim. Biophys. Acta 443:629-634 (1976) [Non-licensed Document 3] Fraley, et al., PNAS 76:3348-3352 (1979) [Non-licensed Document 4] Hope et al., Biochim. Biophys. Acta 812:55-65 (1985) [Non-licensed Document 5] Mayer et al., Biochim. Biophys. Acta 858: 161-168 (1986) [Non-licensed Document 6] Williams et al., PNAS 85:242-246 (1988) [Non-licensed Document 7] Liposomes (Ostro (ed.), 1983, Chapter 1) [Non-licensed Document 8] Hope et al., Chem. Phys. Lip. 40:89 (1986) [Non-licensed Document 9] Gregoriadis, Liposome Technology (1984) [Non-licensed Document 10] Lasic, Liposomes: from Physics to Applications (1993)) [Non-licensed Document 11] ”Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A Wade and PJ Weller [Non-Patent Document 12] Topical drug delivery formulations edited by David Osborne and Antonio Aman, Taylor & Francis [Non-Patent Document 13] Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985) [Non-Patent Document 14] O'Riordan et al (Respir Care, 2002, Nov. 47) [Non-Patent Document 15] JM Stewart and JD Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Company, Rockford, Illinois (1984), in M. Bodanzsky and A. Bodanzsky [Non-Patent Document 16] Cameselle, JC, Ribeiro, JM, 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 Summary of the Invention [Problem to be solved by the invention]

[0007] It is an object of the present invention to overcome at least one of the above-mentioned problems and to provide a natural, food-grade glucose metabolism enhancer. [Means for solving the problem]

[0008] Description of the Invention The pea genome encodes over 70,000 different proteins. Applicant has identified two of these proteins, each of which contains one or more peptides capable of promoting glucose transport in mammalian skeletal muscle (hereinafter referred to as "glucose transport-promoting peptides" or "glucose transport-promoting fragments"). Similarly, of the over 60,000 proteins encoded by the rice genome, Applicant has identified four proteins, each of which contains one or more peptides capable of promoting glucose transport in mammalian skeletal muscle. Compositions containing glucose transport-promoting fragments of the six identified proteins and multiple glucose transport-promoting peptides were found to cause significant increases in cell surface GLUT4 translocation in response to insulin stimulation in vitro (Figures 1-6). Specific plant proteins from which the natural peptides are derived are disclosed herein, for example, in SEQ ID NOs: 1-6. Specific pea proteins from which the peptides are derived are provided in SEQ ID NOs: 1-2, and specific rice proteins from which the peptides are derived are provided in SEQ ID NOs: 3-6. Homologs of these proteins are set forth in SEQ ID NOS: 67-84. Specific peptides first identified in pea proteins are set forth in SEQ ID NOS: 7-46. Specific peptides first identified in rice proteins are set forth in SEQ ID NOS: 47-66. The peptides of the present invention are primarily useful for causing increased glucose uptake in mammalian skeletal muscle and therefore have utility in improving overall muscle health, but also find utility in the treatment or management of metabolic conditions characterized by dysregulated glucose or insulin levels in mammals, such as diabetes, and more particularly in regulating glucose homeostasis and attenuating insulin resistance.

[0009] In a first aspect, the present invention provides peptides comprising a fragment of a protein or a homologue thereof selected from SEQ ID NOs: 1 to 6 or 227 to 234, or a variant of the peptide (hereinafter "peptide of the present invention"), typically 3 to 50 amino acids in length. In one embodiment, the peptide or variant thereof is biologically active. In one embodiment, the peptide or variant thereof has glucose transport promoting activity.

[0010] In one embodiment, the peptide comprises a sequence selected from SEQ ID NOs: 7 to 66 and 85 to 226. In one embodiment, the peptide comprises a sequence selected from SEQ ID NOs: 7, 13 and 51.

[0011] In one embodiment, the peptide consists essentially of a sequence selected from SEQ ID NOs: 7 to 66 and 85 to 226. In one embodiment, the peptide consists essentially of a sequence selected from SEQ ID NOs: 7, 13 and 51.

[0012] In one embodiment, the peptide of the present invention is glucose transport promoting. In another embodiment, the peptide or variant is anti-inflammatory. In another embodiment, the peptide or variant is antibacterial. In another embodiment, the peptide or variant has cell growth or proliferation promoting activity.

[0013] In one embodiment, the fragment has between 8 and 23 amino acids. In one embodiment, the fragment has a charge of -5 and +3.

[0014] Preferably, the C-terminal amino acid is not C, I, K, M, P, T or W.

[0015] Preferably, the N-terminal amino acid is not C, D, H, M, P, T, V, or W.

[0016] Preferably, the C-terminal domain of the fragment does not contain C, M or W.

[0017] Preferably, the N-terminal domain of the fragment does not contain C, M, T or W.

[0018] Preferably, the fragment or peptide does not contain C.

[0019] Preferably, the fragment or peptide does not contain M.

[0020] Preferably, the peptide of the present invention comprises a fragment selected from SEQ ID NOs: 7 to 66, or a biologically active variant of said fragment.

[0021] Preferably, the peptide of the present invention consists of a fragment selected from SEQ ID NOs: 7 to 66, or a biologically active variant of the fragment.

[0022] Preferably, the peptide consists of a sequence selected from SEQ ID NOs: 7-66.

[0023] Preferably, the peptide comprises or consists of a sequence selected from SEQ ID NOs: 7-20.

[0024] Preferably, the peptide comprises or consists of SEQ ID NO:7.

[0025] The present invention also provides modified forms of the peptides of the present invention (modified peptides).

[0026] The present invention also provides a conjugate comprising a peptide of the present invention conjugated to a binding partner.

[0027] [SEQ ID NO: 1 (Pea Protein 1-P13918)] Preferably, the peptide comprises a biologically active fragment of the protein of SEQ ID NO: 1 or a homologue thereof, or a biologically active variant of the fragment. Preferably, the biologically active peptide or fragment is glucose transport stimulatory.

[0028] In one embodiment, the biologically active fragment comprises the sequence LAIPVNR (SEQ ID NO: 235). Examples of biologically active fragments containing the LAIPVNR motif include SEQ ID NOs: 7, 8, 10, 12, and 14.

[0029] In one embodiment, a peptide (or biologically active fragment) of the invention comprises the sequence SFLLSGNQNQ (SEQ ID NO: 236). Examples of biologically active fragments containing this motif include SEQ ID NOs: 9, 11, 13, 16, 17, 190, 191, 192, and 204. Thus, in one embodiment, the invention comprises the sequence:

[0030] In one embodiment, the biologically active fragment comprises the sequence GSLLLPHYN (SEQ ID NO: 237). Examples of biologically active fragments containing this motif include SEQ ID NOs: 18 and 19.

[0031] Preferably, the peptide comprises a biologically active fragment selected from SEQ ID NOs: 7-20, or a biologically active variant of the fragment.

[0032] The present invention also provides a composition comprising at least one, preferably at least two, preferably at least three, preferably at least four, preferably at least five, preferably at least six, preferably at least seven, preferably at least eight, preferably at least nine, or preferably at least ten bioactive peptides of the present invention. When a composition comprises multiple peptides of the present invention, each comprises a different bioactive fragment of SEQ ID NO: 1 (e.g., a fragment of SEQ ID NO: 7-20) or a homolog thereof. Preferably, the composition comprises a first bioactive peptide comprising a first bioactive fragment (or a bioactive variant of the fragment) selected from SEQ ID NO: 7-20 and a second bioactive peptide comprising a second bioactive fragment (or a bioactive variant of the fragment) selected from SEQ ID NO: 7-20. Preferably, the composition comprises a peptide of the present invention comprising substantially all of the fragments of SEQ ID NO: 7-20 or all of the fragments of SEQ ID NO: 7-20.

[0033] Homologues of pea protein 1 (SEQ ID NO: 1) include Vicia fabia, chickpea (Cicer arietinum) and lentil (Lens culinaris) homologues (SEQ ID NOs: 67-69).

[0034] [SEQ ID NO: 2 (pea protein 2-Q9M3X6)] Preferably, the peptide comprises a biologically active fragment of the protein of SEQ ID NO: 2 or a homologue thereof, or a biologically active variant of the fragment. Preferably, the peptide or fragment is glucose transport facilitating.

[0035] Preferably, the peptide comprises a biologically active fragment selected from SEQ ID NOs: 21-46 or a biologically active variant of the fragment.

[0036] The present invention also provides a composition comprising at least one, preferably at least two, preferably at least three, preferably at least four, preferably at least five, preferably at least six, preferably at least seven, preferably at least eight, preferably at least nine, or preferably at least ten bioactive peptides of the present invention. When the composition comprises multiple peptides of the present invention, each peptide comprises a different bioactive fragment of SEQ ID NO:2 (e.g., a fragment of SEQ ID NO:21-46) or a homolog thereof. Preferably, the composition comprises a first bioactive peptide comprising a bioactive fragment selected from SEQ ID NO:21-46 and a second bioactive peptide comprising a bioactive fragment selected from SEQ ID NO:21-46. Preferably, the composition comprises a peptide of the present invention comprising substantially all of the fragments of SEQ ID NO:21-46 or all of the fragments of SEQ ID NO:21-46.

[0037] Homologues of pea protein 2 (SEQ ID NO: 2) include Pisum abyssinicum, Lathyrus annuus, and Vicia villosa (SEQ ID NOs: 70-72).

[0038] [SEQ ID NO: 3 (Rice Protein 1-Q0DEV5)] Preferably, the peptide comprises a biologically active fragment of the protein of SEQ ID NO: 3 or a homologue thereof, or a biologically active variant of the fragment. Preferably, the peptide or fragment is glucose transport facilitating.

[0039] Preferably, the peptide comprises a biologically active fragment selected from SEQ ID NO: 47 or a biologically active variant of that fragment.

[0040] The present invention also provides compositions comprising at least one, preferably at least two, preferably at least three, preferably at least four, preferably at least five, preferably at least six, preferably at least seven, preferably at least eight, preferably at least nine, or preferably at least ten biologically active peptides of the present invention.

[0041] Homologues of rice protein 1 (SEQ ID NO: 3) include Oryza rufipogon, Oryza officinalis, and Hordeum vulgare subsp. vulgare (SEQ ID NOs: 73-75).

[0042] [SEQ ID NO: 4 (Rice Protein 2-P14323)] Preferably, the peptide comprises a biologically active fragment of the protein of SEQ ID NO: 4 or a homologue thereof, or a biologically active variant of the fragment. Preferably, the fragment or peptide is glucose transport facilitating.

[0043] Preferably, the peptide comprises a biologically active fragment selected from SEQ ID NOs: 48-59 or a biologically active variant of the fragment.

[0044] The present invention also provides compositions comprising at least one or more peptides of the invention comprising different biologically active fragments of SEQ ID NO: 4 or a homolog thereof. Preferably, the composition comprises a first peptide comprising a biologically active fragment SEQ ID NO: 48-59 and a second peptide comprising a biologically active fragment SEQ ID NO: 48-59. Preferably, the composition comprises a peptide of the invention comprising substantially all of the fragments of SEQ ID NO: 48-59 or all of the fragments of SEQ ID NO: 48-59.

[0045] Homologues of rice protein 2 (SEQ ID NO: 4) include Oryza brachyantha and Zizania latifolia (SEQ ID NOs: 76-78).

[0046] [SEQ ID NO: 5 (Rice Protein 3-P14614)] Preferably, the peptide comprises a biologically active fragment of the protein of SEQ ID NO: 5 or a homologue thereof, or a biologically active variant of the fragment. Preferably, the fragment or peptide is glucose transport facilitating.

[0047] Preferably, the peptide comprises a biologically active fragment selected from SEQ ID NOs: 60-63 or a biologically active variant of the fragment.

[0048] The present invention also provides a composition comprising at least one, preferably at least two, preferably at least three, preferably at least four, preferably at least five, preferably at least six, preferably at least seven, preferably at least eight, preferably at least nine, or preferably at least ten bioactive peptides of the present invention, each comprising a different bioactive fragment of SEQ ID NO: 5 or a homolog thereof. Preferably, the composition comprises a first bioactive peptide comprising a bioactive fragment selected from SEQ ID NOs: 60-63 and a second bioactive peptide comprising a bioactive fragment selected from SEQ ID NOs: 60-63.

[0049] Homologues of rice protein 3 (SEQ ID NO: 5) include rice japonica (Oryza sativa Japonica Group) and seed storage globulins (SEQ ID NOs: 79 to 81).

[0050] [SEQ ID NO: 6 (Rice Protein 4-P07728)] Preferably, the peptide comprises a biologically active fragment of the protein of SEQ ID NO: 6 or a homologue thereof, or a biologically active variant of the fragment.

[0051] Preferably, the peptide comprises a biologically active fragment selected from SEQ ID NOs: 64-66 or a biologically active variant of the fragment.

[0052] The present invention also provides a composition comprising at least one, preferably at least two, preferably at least three, preferably at least four, preferably at least five, preferably at least six, preferably at least seven, preferably at least eight, preferably at least nine, or preferably at least ten bioactive peptides of the present invention, each of which comprises a bioactive fragment of SEQ ID NO: 6 or a homolog thereof. Preferably, the composition comprises a first bioactive peptide comprising a bioactive fragment selected from SEQ ID NOs: 64-66 and a second bioactive peptide comprising a bioactive fragment selected from SEQ ID NOs: 64-66.

[0053] Homologues of rice protein 4 (SEQ ID NO: 6) include glutelin (rice japonica), glutelin precursor (Zizania latifolia), and globulin (oat) (SEQ ID NOs: 82 to 84).

[0054] The present invention also provides compositions comprising at least one, and preferably a plurality, of biologically active (i.e., glucose transport-promoting) peptides of the present invention, each of which comprises a biologically active (i.e., glucose transport-promoting) fragment of a protein selected from SEQ ID NOs: 1 to 6 or a homolog thereof, or a biologically active (i.e., glucose transport-promoting) variant or fragment thereof.

[0055] Typically, the or each biologically active (i.e., glucose transport-enhancing) peptide of the present invention is selected from or comprises a biologically active (i.e., glucose transport-enhancing) fragment selected from SEQ ID NOs: 7-66 and 85-226, or a biologically active (i.e., glucose transport-enhancing) variant or fragment thereof.

[0056] The present invention also provides compositions comprising at least one, and preferably a plurality, of peptides of the invention, wherein the or each peptide of the invention comprises a biologically active (i.e., glucose transport-enhancing) fragment of a protein selected from SEQ ID NOs: 1-2. Typically, the or each peptide of the invention is selected from or comprises a biologically active (i.e., glucose transport-enhancing) fragment selected from SEQ ID NOs: 7-46, or a biologically active (i.e., glucose transport-enhancing) variant of such a fragment. In one embodiment, a composition comprises a plurality of peptides selected from SEQ ID NOs: 7 and 13 and optionally SEQ ID NOs: 8-12 and 14-46. The present invention also provides compositions comprising peptides comprising substantially all of the fragments of SEQ ID NOs: 7-46, or biologically active (i.e., glucose transport-enhancing) variants of such fragments.

[0057] The present invention also provides compositions comprising at least one, and preferably a plurality, of peptides of the present invention, wherein the or each peptide of the present invention comprises a biologically active (i.e., glucose transport-enhancing) fragment of a protein selected from SEQ ID NOs: 3-6. Typically, the or each peptide of the present invention is selected from or comprises a biologically active (i.e., glucose transport-enhancing) fragment selected from SEQ ID NOs: 47-66, or a biologically active (i.e., glucose transport-enhancing) variant of that fragment. The present invention also provides compositions comprising peptides comprising substantially all of, or a fragment of, SEQ ID NOs: 47-66, or a biologically active (i.e., glucose transport-enhancing) variant of that fragment.

[0058] Preferably, the composition comprises at least two distinct bioactive (ie, glucose transport-enhancing) peptides of the invention.

[0059] Preferably, the composition comprises at least three distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0060] Preferably, the composition comprises at least four distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0061] Preferably, the composition comprises at least five distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0062] Preferably, the composition comprises at least six distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0063] Preferably, the composition comprises at least seven distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0064] Preferably, the composition comprises at least eight distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0065] Preferably, the composition comprises at least nine distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0066] Preferably, the composition comprises at least 10 distinct bioactive (ie, glucose transport-enhancing) peptides of the present invention.

[0067] In one embodiment, the invention includes a composition comprising a peptide containing substantially all or a fragment of SEQ ID NOs: 7-66, or a biologically active (i.e., glucose transport-enhancing) variant of the fragment, or a mixture of biologically active (i.e., glucose transport-enhancing) fragments and variants.

[0068] The present invention also relates to edible products comprising the bioactive (ie, glucose transport enhancing) peptides or fragments of the invention. Preferably, the edible products are man-made.

[0069] The present invention also relates to an edible product comprising a composition of the peptide or fragment of the present invention. Preferably, the edible product is artificial.

[0070] Preferably, the edible product is a food product for human or animal or cellular consumption.

[0071] In one embodiment, the artificial edible product is a nutritional supplement. In one embodiment, the edible product is a sports nutrition product, such as a beverage, snack, or nutritional supplement. In one embodiment, the artificial edible product is a beverage. In one embodiment, the artificial edible product is a bakery product. In one embodiment, the artificial edible product is a dairy product. In one embodiment, the artificial edible product is a snack product. In one embodiment, the artificial edible product is a baked extruded food product. In one embodiment, the artificial edible product is a milk powder. In one embodiment, the artificial edible product is an infant formula product. In one embodiment, the artificial edible product is a confectionery product. In one embodiment, the artificial edible product is yogurt. In one embodiment, the artificial edible product is a yogurt drink. In one embodiment, the artificial edible product is an ice cream product. In one embodiment, the artificial edible product is a frozen food product. In one embodiment, the artificial edible product is a breakfast cereal. In one embodiment, the artificial edible product is bread. In one embodiment, the artificial edible product is a flavored milk drink. In one embodiment, the artificial edible product is a candy bar. In one embodiment, the artificial edible product is tea or a tea product. In one embodiment, the artificial edible product is a baked extruded snack product. In one embodiment, the artificial edible product is a fried snack product. In one embodiment, the artificial edible product is a dietary supplement. In one embodiment, the artificial edible product is a sports nutrition product. In one embodiment, the artificial edible product is a baby food. In one embodiment, the artificial edible product is a specialty food for immunocompromised individuals. In one embodiment, the artificial edible product is a geriatric food.

[0072] The present invention also relates to a peptide of the invention for use in improving muscle condition in a mammal.

[0073] The present invention also relates to a composition of the present invention for use in improving muscle condition in a mammal.

[0074] The present invention also relates to peptides of the invention for use in promoting muscle recovery, generally after exercise.

[0075] The present invention also relates to compositions of the present invention for use in promoting muscle recovery, generally after exercise.

[0076] The present invention also relates to a peptide of the invention for use in maintaining or restoring muscle health (eg, lean tissue mass) in a mammal.

[0077] The present invention also relates to compositions of the peptides of the invention for use in maintaining or restoring muscle health (eg, lean tissue mass) in a mammal.

[0078] The present invention also relates to a peptide of the invention for use in enhancing physical performance.

[0079] The present invention also relates to the compositions of the present invention for use in enhancing physical performance.

[0080] The present invention also relates to a peptide of the invention for use in the prevention or treatment of a metabolic disorder characterized by dysregulated glucose or insulin levels in a mammal. In one embodiment, the disorder is diabetes.

[0081] The present invention also relates to a composition of the present invention for use in the prevention or treatment of a metabolic disorder characterized by dysregulated glucose or insulin levels in a mammal. In one embodiment, the disorder is diabetes.

[0082] The present invention also relates to a peptide of the invention for use in improving glycemic control in a mammal.

[0083] The present invention also relates to a composition of the present invention for use in improving glycemic control in a mammal.

[0084] The present invention also relates to a peptide of the invention for use in one or more of reducing plasma glucose levels, regulating glucose homeostasis, and attenuating insulin resistance in a mammal.

[0085] The present invention also relates to compositions of the present invention for use in one or more of reducing plasma glucose levels, regulating glucose homeostasis, and attenuating insulin resistance in a mammal.

[0086] The present invention also relates to a peptide of the invention for use in the treatment or prevention of a disease or condition characterized by lethargy or low energy levels.

[0087] The present invention also relates to compositions of the peptides of the invention for use in the treatment or prevention of diseases or conditions characterized by lethargy or low energy levels.

[0088] The present invention also relates to pharmaceutical compositions comprising a peptide of the present invention in combination with a pharmaceutically acceptable carrier. In one embodiment, the peptide is a glucose transport enhancing peptide.

[0089] The present invention also relates to pharmaceutical compositions comprising a composition of the peptides of the present invention in combination with a pharmaceutically acceptable carrier.

[0090] The present invention also relates to edible products, such as foods, including dairy or non-dairy products, solid foods or beverages, food additives, or nutritional supplements, comprising the peptides or compositions of the present invention. The dairy products can be milk, cheese, or yogurt. In one embodiment, the food is a sports nutrition product. The food can contain any amount of the composition of the present invention, for example, from 0.1% to 30% (w / w).

[0091] The peptides of the present invention are preferably used in topical cosmetic or pharmaceutical compositions of the present invention at cosmetically or pharmaceutically effective concentrations to achieve the desired effect, between 0.00000001% (by weight) and 20% (by weight), preferably between 0.000001% (by weight) and 15% (by weight), more preferably between 0.0001% (by weight) and 10% (by weight), and even more preferably between 0.0001% (by weight) and 5% (by weight) of the total weight of the composition. Ideally, the peptides of the present invention are used in an amount of about 0.00001% w / w to about 0.5% w / w [0.1 to 5000 ppm], more preferably 0.00005 w / w to about 0.05 w / w [0.5 to 500 ppm], and most preferably about 0.0001 w / w to about 0.01 w / w [1 to 100 ppm] of the composition. Ideally, the peptides of the present invention are used in an amount of from about 0.0001% w / w to about 0.004% w / w of the composition.

[0092] For the peptide compositions of the present invention, the usual daily dosage may be 0.2 g to 100 g, but when administered as a food or medical diet for specific medical purposes, the daily dose may be 50 to 500 g per day.

[0093] Dosages of the compositions of the present invention for use in foods and food supplements (i.e., edible compositions) will broadly range from 0.2 to 100 g / day. In one embodiment, the daily dosage is 1 to 10 g / day, ideally about 3 to 8 g / day. In one embodiment, the daily dosage is 10 to 20 g / day. In one embodiment, the daily dosage is 20 to 30 g / day. In one embodiment, the daily dosage is 30 to 40 g / day. In one embodiment, the daily dosage is 10 to 100 g / day. In one embodiment, the daily dosage is about 5 g / day, ideally about 3 to 8 g / day. In one embodiment, the dosage is 2 to 1000 mg / kg of body weight / day. In one embodiment, the dosage is 10 to 500 mg / kg of body weight / day. In one embodiment, the dosage is 10 to 100 mg / kg of body weight / day. In one embodiment, the dosage is 30-70 mg / day / kg body weight. The dosage of the peptides of the present invention for dietary supplements can be 0.00001 mg to 0.01 mg per day or dose.

[0094] A food may be a Food for Specific Medicinal Purposes (FSMP), which is defined as a food that is specially formulated, processed, and intended for the dietary management of a disease, injury, or medical condition in an individual being treated under medical supervision. These foods are intended for the exclusive or partial feeding of persons whose nutritional requirements cannot be met by the normal diet.

[0095] The present invention also provides topical compositions comprising the peptides of the present invention. It will be understood that the topical composition may comprise multiple peptides, fragments, and / or variants. In one embodiment, the topical composition comprises substantially all of the peptides. In one embodiment, the topical composition comprises substantially all of the variants. The topical compositions of the present invention may be present in a formulation selected from the group including creams, multiple emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balsams, foams, lotions, gels, cream gels, hydroalcoholic solutions, hydroglycolic solutions, beauty products, personal care products, hydrogels, liniments, serums, soaps, dusting powders, pastes, semisolid formulations, liniments, serums, shampoos, conditioners, ointments, optional rinse-off formulations, talc, mousses, powders, sprays, aerosols, solutions, suspensions, emulsions, syrups, elixirs, polysaccharide films, patches, gel patches, bandages, adhesive systems, water-in-oil emulsions, oil-in-water emulsions, and silicone emulsions.

[0096] In one embodiment of the present invention, the emulsion contains lipid or oil. The emulsion can be, but is not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsion. The emulsion can contain a moisturizing agent. The emulsion can contain an antifoaming agent such as silicone. The emulsion can have any suitable viscosity. The emulsion can further contain an emulsifier and / or an antifoaming agent. Methods for preparing emulsions are known to those skilled in the art.

[0097] The topical composition of the present invention can be incorporated into a medical device for administration. Such devices can include, but are not limited to, fabrics, patches, bandages, gauges, socks, tights, underwear, bandages, gloves, masks, adhesive patches, non-adhesive patches, occlusive patches, and microelectric patches or suitable adhesive systems. In such an embodiment, the device is in direct contact with a keratin layer such as the skin, thus releasing the peptide of the present invention. It will be understood that the topical composition can be incorporated into any suitable form as detailed herein. For example, the topical composition or peptide of the present invention can be incorporated into the device or 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 or on the surface of the device. The device can be adapted for adhesion or attachment to the skin.

[0098] In one embodiment, the device is adapted to release a constant amount of the composition or peptide of the present invention. It will be understood that the amount of composition contained in the sustained release system will depend, for example, on the location where the composition is to be administered, the kinetics and duration of the release of the composition of the present invention, and 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, or by body moisture, skin pH, or body temperature.

[0099] In one embodiment of the present invention, the topical composition may further comprise at least one cosmetically or pharmaceutically acceptable excipient. The term "excipient" may be used interchangeably with "functional ingredient" or "additive." It should be understood that the topical composition of the present invention may be administered alone, but is generally administered in a mixture with a cosmetic or pharmaceutical excipient. Cosmetically or pharmaceutically acceptable excipients are well known in the art, and any known excipient may be used, provided that it is suitable for topical administration and dermatologically acceptable without excessive toxicity, incompatibility, and / or allergic reaction.

[0100] Preferably, any excipients included are present in trace amounts. The amount of excipient included depends on many factors, including the type of excipient used, the nature of the excipient, the component(s) of the topical composition, the amount of active substance 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 the present invention.

[0101] In one embodiment of the present invention, the excipient may be a suitable diluent, carrier, binder, lubricant, suspending agent, coating agent, preservative, stabilizer, dye, vehicle, solubilizer, base, emollient, emulsifier, fragrance, moisturizer, and / or surfactant.

[0102] Examples of suitable diluents include, but are not limited to, any of the diluents disclosed in U.S. Patent No. 5,629,997 or U.S. Patent No. 5,629,997. Examples include ethanol, glycerol, and water.

[0103] Examples of suitable carriers include, but are not limited to, lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and any suitable carrier disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999.

[0104] Examples of suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, carboxymethylcellulose and polyethylene glycol and any suitable binder disclosed in U.S. Patent No. 5,629,999 or U.S. Patent No. 5,629,999.

[0105] Examples of suitable lubricants include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride and any suitable lubricant disclosed in U.S. Patent No. 5,629,999 or U.S. Patent No. 5,629,999.

[0106] The carrier may be any suitable carrier known in the art or disclosed in U.S. Patent No. 5,999,237 or U.S. Patent No. 5,999,237. In some embodiments, the carrier may comprise a liquid such as water, oil, or surfactant, including, but not limited to, those of petroleum, animal, vegetable, or synthetic origin; a polymer; an oil such as peanut oil, mineral oil, castor oil, or soybean oil; an alcohol; a polysorbate; a sorbitan ester; an ether sulfate; a sulfate; a betaine; a glycoside; a maltoside; a fatty alcohol; nonoxynol; a polixamer; polyoxyethylene; a polyethylene glycol; dextrose; glycerol; or digitonin. It is understood that the carrier is dermatologically acceptable. Preferred carriers include emulsions such as oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in-water-in-silicone emulsions. The emulsion may further contain an emulsifier and / or an antifoaming agent.

[0107] In one embodiment of the present invention, topical composition can further comprise one or more additional components.Topical composition of the present invention can be administered continuously, simultaneously or sequentially with one or more other additional drugs.Such additional components can be beneficial to be included in topical composition or beneficial according to the intended use of topical composition.Additional components can be active or functional or both.

[0108] Examples of such additional ingredients include, but are not limited to, one or more cleansing agents, conditioning agents, sunscreens, pigments, moisturizers, thickeners, gelling agents, essential oils, astringents, dyes, anti-caking agents, anti-foaming agents, binders, additives, buffers, chelating agents, topical 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, therapeutic agents, thickeners, vitamins, colorants, formulations, preservatives, anti-foaming agents, buffers, astringents, polymers, pH adjusters, deodorizing agents, or any other dermatologically acceptable carrier or surfactant.

[0109] It should be understood that a listed additional ingredient may provide more than one benefit. The classification given herein is merely for clarity and convenience and is not intended to limit the additional ingredient to that particular application or category listed.

[0110] Any additional ingredients must be suitable for application to the skin without undue toxicity, incompatibility and / or allergic reaction.

[0111] In some embodiments, the additional ingredient has glucose transport activity or supports glucose transport activity. In some embodiments, the additional ingredient has anti-inflammatory activity or supports anti-inflammatory activity. In some embodiments, the additional ingredient has anti-aging activity or supports anti-aging activity. In some embodiments, the additional ingredient is for the health and / or development of the keratin layer, skin health and / or development, and / or muscle health, recovery, and / or development. The active agent can be a pharmacological enhancer. Such active agents are known and commercially available. In such cases, the topical composition of the present invention can be administered continuously, simultaneously, or sequentially with one or more other active agents.

[0112] In some embodiments, the additional ingredient can 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, plant and marine extracts, anti-acne actives, anti-wrinkle or anti-atrophy actives, antioxidants / radical scavengers, chelating agents, flavonoids, anti-inflammatory agents, anti-seborrheic agents, topical anesthetics, tanning actives, skin lightening agents, skin healing agents, bisabolol, antibacterial or antifungal actives, sunscreen actives, particulate materials, conditioning agents, structuring agents, thickeners.

[0113] The desquamation active can be any suitable agent that enhances the appearance or texture of the skin, such as those disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999.

[0114] Examples of anti-acne actives include resorcinol, salicylic acid, erythromycin, zine, sulfur, and benzoyl peroxide, as disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999.

[0115] Examples of thickeners are as disclosed in Patent Document 1 or Patent Document 2, and include carboxylic acid polymers, cross-linked polyacrylate polymers, polyacrylamide polymers, and polysaccharides.

[0116] Examples of conditioning agents are as disclosed in US Pat. No. 5,699,299 or US Pat. No. 5,699,299 and include humectants, moisturizers or skin conditioners.

[0117] Examples of structuring agents are as disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999, and include any agent that provides rheological characteristics to the composition and contributes to the stability of the composition.

[0118] Any suitable antibacterial or antifungal active agent may be used, examples of which are disclosed in U.S. Patent No. 5,629,999 or U.S. Patent No. 5,629,999. Such active agents are capable of destroying microorganisms or preventing their growth or action. Examples include, but are not limited to, beta-lactam drugs, quinolones, tetracyclines, erythromycin, streptomycin sulfate, salicylic acid, and benzoyl peroxide.

[0119] Examples of particulate materials include metal oxides. Examples of anti-lipid deposition agents include xanthines. Examples of tanning actives include 1,3-dihydroxy-2-propanone and those disclosed in U.S. Patent No. 5,629,997 or U.S. Patent No. 5,629,997. Examples of local anesthetics include benzocaine, lidocaine, and bupivacaine and those disclosed in U.S. Patent No. 5,629,997 or U.S. Patent No. 5,629,997.

[0120] Examples of skin lightening agents include any agent known in the art, such as kojic acid, ascorbic acid, and those disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999.

[0121] Examples of sunscreen actives include any suitable organic or inorganic sunscreen actives, including metal oxides, 2-ethylhexyl-p-methoxycinnamate, and those disclosed in U.S. Patent No. 5,629,999 or U.S. Patent No. 5,629,999.

[0122] Examples of skin healing agents include panthenoic acid, as disclosed in US Pat. No. 5,627,999 or US Pat. No. 5,627,999.

[0123] Examples of anti-inflammatory agents include any agent that enhances the appearance, brightness, or color of the skin, including, but not limited to, corticosteroids, hydrocortisone, nonsteroidal agents such as ibuprofen and aspirin, and those disclosed in U.S. Patent No. 5,627,999 or U.S. Patent No. 5,627,999.

[0124] Examples of flavonoids include flavanones, methoxyflavonones, unsubstituted chalcones and mixtures thereof, as well as those disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999.

[0125] Examples of enzymes include lipase, protease, catalase, superoxide dismutase, amylase, peroxidase, glucuronidase, ceramidase, and hyaluronidase. Examples of enzyme inhibitors include trypsin inhibitor, Bowman-Birk inhibitor, chymotrypsin inhibitor, plant extract, flavonoid, quercetin chalcone, and those disclosed in Patent Document 1 or Patent Document 2, and mixtures thereof. Examples of enzyme activators include coenzyme A, Q10 (ubiquinone), glycyrrhizin, berberine, chrysin, and those disclosed in Patent Document 1 or Patent Document 2, and mixtures thereof.

[0126] Examples of anti-wrinkle or anti-atrophy actives include sulfur-containing D and L amino acids, especially N-acyl derivatives such as N-acetyl-L-cysteine, hydroxyl acids, phytic acid, lipoic acid, lysophosphatidic acid, skin exfoliants, vitamin B3, retinoids and those disclosed in US Pat. No. 5,629,999 or US Pat. No. 5,629,999 and mixtures thereof.

[0127] The antioxidant / radical scavenger agent can be any agent useful in providing protection from UV radiation or other environmental agents that can cause skin damage, such as those disclosed in U.S. Patent No. 5,999,297 or U.S. Patent No. 5,999,297. Examples of antioxidant / radical scavengers include ascorbic acid, its salts and derivatives (vitamin C), tocopherol, its salts and derivatives (vitamin E), butylated hydroxylbenzoic acid and its salts, peroxides, gallic acid and alkyl esters, sorbic acid, lipoic acid, amines, lysine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, methionine, proline, superoxide dismutase, silymarin, tea extracts, and mixtures thereof.

[0128] Examples of chelating agents include EDTA, NTA, hydroxamic acid, phytic acid, lactoferrin, and those disclosed in Patent Document 1 or Patent Document 2, and mixtures thereof. A chelating agent refers to an agent that can remove metal ions by forming a complex so that the metal ions cannot participate in or catalyze chemical reactions. Chelating agents are useful for protection from UV radiation or other environmental agents that can cause skin damage.

[0129] It will be understood that multiple additional ingredients may be added. The amount of additional ingredient may be about 0.001% to about 50% by 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% by weight of the composition. The amount of additional ingredient included depends on numerous factors, including the type of additional ingredient used, the nature of the additional ingredient, the ingredient(s) of the topical composition, the amount of active substance 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 the present invention.

[0130] The topical composition may be alcohol-free.

[0131] In some embodiments of the present invention, the composition further comprises one or more additional active agents in addition to the peptide of the present invention (also known as the active agent of the composition). Additionally or alternatively, the composition may be administered with one or more other additional active agents. Typically, such additional active agents are present only in trace amounts. In some embodiments, no additional active agents may be present in the composition. The amount of additional active agent included depends 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 agent 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 peptide of the present invention.

[0132] It should be understood that an ingredient that is considered to be an "active" ingredient in one product may be a "functional" or "excipient" ingredient in another, and vice versa. It will be understood that some ingredients may serve a dual role as both an active ingredient and a functional or excipient ingredient.

[0133] Examples of additional active agents include glucose transport promoters, skin nutritional supplements, agents for treating and / or caring for skin, anti-inflammatory agents, anti-aging agents, cell growth promoters, and pharmacological enhancers.Such agents are well known in the art, and it is understood that any suitable additional active agent can be used.Additional active agents for treating and / or healing skin can include collagen synthesis agents, retinoids, exfoliants, anti-lipid deposition agents, elastase inhibitors, melanin synthesis stimulators or inhibitors, self-tanning agents, anti-aging agents, antibacterial agents, antifungal agents, fungistatic agents, bactericides, and healing agents.Active agents also include anti-inflammatory agents.

[0134] Any additional active agent must be suitable for application to the skin without undue toxicity, incompatibility and / or allergic reaction.

[0135] It will be understood that the classifications given herein are for clarity and convenience only and are not intended to limit the additional ingredients, excipients or active substances to that particular application or category listed.

[0136] In a particularly preferred embodiment, the method and use of the present invention comprises administering the peptide or composition of the present invention in combination with one or more other active agents, such as existing growth promoters or pharmacological enhancers available on the market.In such cases, the compound of the present invention can be administered continuously, simultaneously or sequentially with one or more other active agents.

[0137] The effect of the present invention is achieved by topically applying or administering the topical composition of the present invention described herein to humans, animals or patients who need treatment or care.Topical delivery preferably refers to delivery to keratin layers such as skin, hair and / or nails, but can also refer to delivery to the body cavity lined with epithelial cells, such as lungs or respiratory tract, gastrointestinal tract, buccal cavity.Effect can be limited to the surface of the skin, or can be intradermal, or can be a combination of both.

[0138] The topical compositions of the present invention are administered in a cosmetically or pharmaceutically effective amount. In other words, in an amount that is non-toxic but sufficient to provide the desired effect. It will be understood that a person skilled in the art would be able to determine the appropriate dosage of the topical compositions of the present invention to administer without undue experimentation. Alternatively, a physician will determine the actual dosage that is most suitable for a patient depending on the individual condition, the disease or disorder to be treated or cured, and the age, weight, and / or health of the individual. This will depend on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the individual condition, and the therapy the individual is undergoing. Of course, there may be individual cases where higher or lower dosage ranges are merited, and such are within the scope of the present invention. For example, the composition may be administered at a dose of 0.1 to 30 mg / kg, more preferably 0.1 to 20 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, preferably 0.01 to 50 mg / kg body weight, such as 0.1 to 5 mg / kg body weight. In an exemplary embodiment, one or more doses of 10 to 300 mg / day, or more preferably 10 to 150 mg / day, are administered to the patient. The amount and frequency are as optimal for the purpose. The frequency of application or administration can vary widely depending on the needs of each subject, with recommended application or administration ranges from once a month to 10 times a day, preferably once a week to four times a day, more preferably three times a week to three times a day, and even more preferably once or twice a day.

[0139] In a preferred embodiment, repeated use of the topical composition is provided.

[0140] The topical composition may be applied by rubbing or massaging into the keratinous tissue, skin, or area of ​​the body to be treated or cared for. In some embodiments, the composition remains on the area of ​​the body or is not removed therefrom. In other embodiments, the composition is removed after a period of time, such as, but not limited to, about 2 to 60 minutes, about 5 to 30 minutes, and preferably about 10 to 20 minutes. The composition may be removed immediately after application. In some embodiments of the present invention, the composition of the present invention may be applied to the area to be treated by a means to achieve greater penetration of the composition and / or peptide of the present invention, such as, but not limited to, iontophoresis, sonophoresis, electroporation, microelectric patching, mechanical pressure, osmotic gradient, occlusive therapy, microinjection or pressure-assisted needle-free injection, such as oxygen pressure-assisted injection, or any combination thereof.

[0141] The peptides of the present invention are used in the topical cosmetic or pharmaceutical compositions of the present invention in a preferred form at a cosmetically or pharmaceutically effective concentration to achieve the desired effect, between 0.00000001% (by weight) and 20% (by weight), preferably between 0.000001% (by weight) and 15% (by weight), more preferably between 0.0001% (by weight) and 10% (by weight), and even more preferably between 0.0001% (by weight) and 5% (by weight) of the total weight of the composition.

[0142] In some embodiments of the present invention, the compositions may be delivered in any one of liposomes, mixed liposomes, oleosomes, niosomes, ethosomes, millicapsules, capsules, macrocapsules, nanocapsules, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, surfactant mixed micelles, surfactant-phospholipid mixed micelles, millispheres, spheres, lipospheres, particles, nanospheres, nanoparticles, milliparticles, solid nanoparticles, and microemulsions, including water-in-oil microemulsions with reverse micelle internal structures, and nanoemulsions, microspheres, and microparticles.

[0143] Various methods are available for preparing liposomes. See, e.g., (Illegible text - likely OCR error) ...

[0144] These delivery systems can be adapted to achieve greater penetration of the compounds and / or peptides of the present invention. This can improve pharmacokinetics and pharmacodynamics. The delivery system can be a sustained release system in which the compounds or peptides of the present invention are gradually released for a certain period of time, preferably at a constant release rate over a certain period of time. The delivery system is prepared by a method known in the art. The amount of peptide contained in the sustained release system depends on the location and release period of the composition to be delivered and the type of condition, disease and / or disorder to be treated or cared for.

[0145] The topical compositions of the present invention may be for human and animal use in human and veterinary medicine.

[0146] The topical compositions of the present invention may be used for pharmaceutical, personal care and / or cosmetic uses.

[0147] The compositions may be used to treat or care for any disease, disorder or condition of the skin, including, but not limited to, itches, dermatitis, allergic dermatitis, eczema, spongiosis, edema, skin cancer, ulcers, acne, scars, cellulitis, elastosis, keratosis, rosacea, varicose veins, inflammatory disorders.

[0148] Topical composition can be used to treat or care for the visible signs of aging, including but not limited to wrinkles, lines and dark circles, dryness, fine lines, blemishes, red spots, loose skin, and the conditions caused by sun exposure, stress, pollution and / dietary restrictions, including sunburn.Topical composition can also be used to delay, slow down or inhibit the skin or the occurrence of aging.Composition can be administered by medical device such as plaster or patch as described herein.

[0149] This topical composition can be used to treat or care for wounds in mammals.In another embodiment, this topical composition is used for treating or preventing the disease or condition that is characterized by damaged epithelial cells or tissue and / or damaged dermis or epithelial cells or tissue.The disease can be but is not limited to cancer and trauma.

[0150] The topical compositions may be used in the treatment or prevention of diseases or conditions characterized by lethargy or low energy levels, to treat or care for any muscle condition, to improve muscle condition in mammals, typically to promote muscle recovery after exercise, to maintain or restore muscle health (e.g., lean tissue mass) in mammals, and to enhance physical performance.

[0151] The topical compositions can be used to promote tissue growth, epithelial tissue growth, skin growth, organ growth, and other biological growth. The skin may have normal and / or abnormal pathology.

[0152] The topical compositions may also be used to treat or care for any inflammatory disorder.

[0153] A further aspect of the present invention relates to pharmaceutical compositions comprising a peptide of the present invention or a composition of a peptide of the present invention mixed with one or more pharmaceutically acceptable diluents, excipients, or carriers. While the peptides and compositions of the present invention can be administered alone, they are generally administered in admixture with a pharmaceutical carrier, excipient, or diluent, particularly for human therapy. The pharmaceutical compositions may be for human and animal use in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in Non-Patent Document 11. In particular, topical delivery formulations are described in Non-Patent Document 12, the entire contents of which are incorporated herein by reference. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Non-Patent Document 13. Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of suitable diluents include ethanol, glycerol, and water. The choice of pharmaceutical carrier, excipient, or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions can contain any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s) as, or in addition to, the carrier, excipient, or diluent. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Preservatives, stabilizers, dyes, and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0154] The peptides or compositions of the present invention may be adapted for topical, oral, rectal, parenteral, intramuscular, intraperitoneal, intraarterial, intrabronchial, subcutaneous, intradermal, intravenous, intranasal, vaginal, buccal, or sublingual administration. For oral administration, compressed tablets, pills, tablets, gels, drops, and capsules are particularly used. Preferably, these compositions contain 1 to 250 mg, more preferably 10-100 mg, of active ingredient per dose. Other forms of administration include solutions or emulsions that may be injected intravenously, intraarterially, subcutaneously, intradermally, intraperitoneally, or intramuscularly and are prepared from sterile or sterilizable solutions. Pharmaceutical compositions of the present invention may be in the form of suppositories, vaginal rings, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions, or dusting powders. The compositions of the present invention may be formulated for topical delivery. Topical delivery generally refers to delivery to the skin, but can also refer to delivery to epithelial-lined body cavities, such as the lungs or respiratory tract, the gastrointestinal tract, and the buccal cavity. In particular, topical delivery formulations are described in Non-Patent Document 12, the entire contents of which are incorporated herein by reference. Compositions or formulations for delivery to the respiratory tract are described in Non-Patent Document 14, Patent Document 13, Patent Document 14, Patent Document 15, and Patent Document 16. Compositions and formulations for delivering active agents to the ileum, particularly the proximal ileum, include microparticles and microencapsulated formulations in which the active agent is encapsulated within a protective matrix formed from polymers or milk proteins that are acid-resistant but tend to dissolve in the more alkaline environment of the ileum. Examples of such delivery systems are described in Patent Documents 17 and 18. An alternative to transdermal administration is through the use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol 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 stabilizers and preservatives as may be required.

[0155] Injectable material forms may contain between 10 and 1000 mg, preferably between 10 and 250 mg, of active ingredient per dose.

[0156] Compositions may be formulated in unit dosage form, ie, in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.

[0157] Those skilled in the art can easily determine the appropriate dose of one of the compositions to be administered to a subject without undue experimentation. Typically, a physician will determine the actual dosage that is most suitable for an individual patient, and it will depend on a variety of factors, including the activity of the particular compound, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the individual's condition, and the therapy the individual is undergoing. The dosages disclosed herein are exemplary of the average case. Of course, there can be individual cases where higher or lower dosage ranges are merited, and such are within the scope of this invention. If necessary, the agent can be administered at a dose of 0.1 to 10 mg / kg, more preferably 0.01 to 30 mg / kg body weight, such as 0.1 to 1 mg / kg body weight. In an exemplary embodiment, one or more doses of 10 to 300 mg / day, or more preferably 10 to 150 mg / day, are administered to a patient for the treatment of an inflammatory disorder.

[0158] In a particularly preferred embodiment, the methods and uses of the present invention include administering the peptide or composition of the present invention in combination with one or more other active agents, such as existing anti-inflammatory drugs or pharmacological enhancers available on the market. In such cases, the compound of the present invention can be administered continuously, simultaneously, or sequentially with one or more other active agents.

[0159] In one embodiment of the present invention, the peptide of the present invention can be administered in the form of a conjugate comprising the peptide, and optionally 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. In one embodiment, the peptide can be modified to replace one or more amino acids with amino acids used to attach to the partner molecule. For example, an amino acid can be replaced with a lysine residue for the purpose of conjugating a partner molecule such as a PEG molecule.

[0160] definition All publications, patents, patent applications and other references mentioned herein are incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference and the contents of which were set forth in full.

[0161] As used herein, unless otherwise indicated, the following terms shall have the following meanings, in addition to any broader (or narrower) meaning by which such terms are used in the art: Unless otherwise required by context, the use of the singular herein should be read to include the plural, and vice versa. The term "a" or "an" when used in reference to an entity should be read to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0162] As used herein, the term "comprise" or variations thereof, such as "comprises" or "comprising," should be read to indicate the inclusion of any enumerated integer (e.g., feature, element, characteristic, property, method / process step, or limitation) or group of integers (e.g., feature, element, feature, property, method / process step, or limitation), but not the exclusion of any other integer or group of integers. Thus, as used herein, the term "comprising" is inclusive or open-ended and does not exclude additional, unenumerated integers or method / process steps.

[0163] As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, disorder, pathology, condition, or syndrome in which physiological function is impaired, regardless of the nature of the etiology (or indeed whether the etiological basis of the disease has been established). Thus, it encompasses conditions resulting from infection, trauma, injury, surgery, radiation ablation, poisoning, or nutritional deficiency.

[0164] As used herein, the term "treatment" or "treating" refers to an intervention (e.g., administering a drug to a subject) that cures, alleviates, or relieves the symptoms of a disease, or eliminates (or mitigates) its cause(s) (e.g., reducing the accumulation of pathological levels of lysosomal enzymes). In this context, the term is used interchangeably with the term "therapy."

[0165] Furthermore, the term "treatment" or "treating" refers to an intervention (e.g., administration of a drug to a subject) that prevents or slows the onset or progression of a disease, or reduces its incidence (or eradicates) within the treated population. In this instance, the term "treatment" is used synonymously with the term "prophylaxis."

[0166] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount that can be administered to a subject without excessive toxicity, irritation, allergic reactions, or other problems or complications, commensurate with the benefit / risk ratio, but sufficient to provide the desired effect, e.g., treatment or prevention, as indicated by permanent or temporary improvement of the subject's condition. The amount will vary from subject to subject, depending on the individual's age and general condition, the mode of administration, and other factors. Therefore, it is not possible to specify an exact effective amount, but those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and general background knowledge. In this context, therapeutic results include eradicating or alleviating symptoms, reducing pain or discomfort, prolonging survival, improving mobility, and other markers of clinical improvement. The therapeutic result does not necessarily have to be a complete cure.

[0167] The term "human or animal" should be understood to include humans, mammals, and other non-mammals, such as fish. The human can be an infant, toddler, child, adolescent, adult, or elderly human. In one embodiment of the present invention, the human is an elderly human, e.g., 55 years of age or older. In one embodiment, the human is an elderly human experiencing a decline in lean tissue mass. In one embodiment, the human is an athlete. In one embodiment, the human is a pregnant woman. In one embodiment, the human suffers from lethargy or a perceived lack of energy.

[0168] As used herein, the term "peptide" refers to a polymer typically composed of 5 to 50 amino acid monomers linked via peptide bonds. Peptides of and for use in the present invention (including fragments and variants thereof) can be produced completely or partially by chemical synthesis or by expression from nucleic acids. For example, peptides of and for use in the present invention can be readily prepared according to well-established standard solution-phase or, preferably, solid-phase peptide synthesis methods known in the art (see, e.g., J. Am. Chem. Soc. 1999, 144:131-132). If necessary, any of the peptides used in the present invention can be chemically modified to increase their stability. Chemically modified peptides or peptide analogs include any functional chemical equivalent of a peptide characterized by its increased stability and / or efficacy in vivo or in vitro for practicing the present invention. The term peptide analog also refers to any amino acid derivative of a peptide as described herein. Peptide analogs can be produced by procedures including, but not limited to, side chain modifications, the incorporation of unnatural amino acids and / or derivatives thereof during peptide synthesis, and the use of crosslinking agents and other methods that impose conformational constraints on the peptide or its analog. Examples of side chain modifications include reductive alkylation by reaction with an aldehyde followed by reduction with NaBH4, amidation with methyl acetimidate, acetylation with acetic anhydride, carbamylation of the amino group with cyanic acid, trinitrobenzylation of the amino group with 2,4,6-trinitrobenzenesulfonic acid (TNBS), alkylation of the amino group with succinic anhydride and tetrahydrophthalic anhydride, and pyridoxylation of lysine with pyridoxa-5'-phosphate followed by reduction with NABH4. The guanidino group of arginine residues can be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal, and glyoxal. Carboxyl groups can be modified by carbodiimide activation via o-acylisourea formation followed by subsequent derivatization, for example, to the corresponding amide.Sulfhydryl groups can be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide, performic acid oxidation to cysteic acid, formation of mixed disulfides with other thiol compounds, reaction with maleimide, maleic anhydride, or other substituted maleimides, formation of mercury derivatives with 4-chloromercurybenzoic acid, 4-chloromercuryphenylsulfonic acid, phenylmercury chloride, 2-chloromercuric-4-nitrophenol, and other mercuric acids, and carbamylation with cyanic acid at alkaline pH. Tryptophan residues can be modified, for example, by oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulfonyl halides. Tyrosine residues can be altered by nitration with tetranitromethane to form 3-nitrotyrosine derivatives. Modification of the imidazole ring of histidine residues can be achieved 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, norleucine, 4-aminobutyric 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-thienylalanine, and / or the use of D-isomers of amino acids. Peptide structural modifications include the creation of retro-inverso peptides containing reverse sequences encoded by D-amino acids.

[0169] "Modified peptide": In one embodiment of the present invention, the peptide is a modified peptide. The term "modified peptide" is used synonymously with the term "derivative of a peptide." Modified peptides include peptides substituted with one or more groups as defined herein. The modification can be any modification that provides the peptides and / or compositions of the present invention with increased cell penetration ability. The modification can be any modification that increases the half-life of the compositions or peptides of the present invention. In one embodiment, the group is a protecting group. The protecting group can be an N-terminal protecting group, a C-terminal protecting group, or a side chain protecting group. The peptide can have one or more of these protecting groups. Those skilled in the art are aware of suitable techniques for reacting amino acids with these protecting groups. These groups can be added by preparative methods known in the art, for example, the methods outlined in paragraphs

[0104] to

[0107] of Patent Document 19. The group can remain on the peptide or can be removed. The protecting group can be added during synthesis. In one embodiment of the present invention, the peptides may be substituted with one or more groups selected from hydroxyl, amino, aminoacyl, sulfate, or sulfide groups, saturated or unsaturated, straight or branched, long or short chains having 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, isostearic acid, elaidic acid, 2-ethylhexane 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. If substituted, they are preferably substituted with hydroxyl or sulfur-containing groups such as, but not limited to, SO3H, SH, or SS. In one embodiment of the present invention, the peptides are R1-X-R2. The R1 and / or R2 groups are attached to the amino terminus (N-terminus) and carboxyl terminus (C-terminus) of the peptide sequence, respectively. In one embodiment, the peptide is R1-X.Alternatively, the peptide is X-R2. Preferably, R1 is H, C. 1~4 In one embodiment, R1 is selected from the group formed by H, acyclic substituted or unsubstituted aliphatic groups, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), and R5-CO-, wherein R5 is H, acyclic substituted or unsubstituted aliphatic groups, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and R2 is selected from the group formed by -NR3R4, -OR3 and -SR3, where R3 and R4 are independently selected from the group formed by H, acyclic substituted or unsubstituted aliphatic groups, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl, with the proviso that R1 and R2 are not α-amino acids. According to another preferred embodiment, R2 is -NR3R4, -OR3 or -SR3, where R3 and R4 are independently H, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, t-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C 24 Cycloalkyl, substituted or unsubstituted C5-C 24 Cycloalkenyl, substituted or unsubstituted C8-C 24 Cycloalkynyl, substituted or unsubstituted C6-C 30 Aryl, substituted or unsubstituted C7-C 24aralkyl, 3-10 membered substituted or unsubstituted heterocyclyl rings, and substituted or unsubstituted heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than carbon, wherein the alkyl chain is of 1 to 6 carbon atoms. Optionally, R3 and R4 may be joined by a saturated or unsaturated carbon-carbon bond to form a ring together with the nitrogen atom. More preferably, R2 is -NR3R4 or -OR3, where R3 and R4 are independently H, substituted or unsubstituted C1-C 24 Alkyl, substituted or unsubstituted C2-C 24 Alkenyl, substituted or unsubstituted C2-C 24 Alkynyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 15

[0023] Preferably, R3 and R4 are selected from the group formed by aryl and 3- to 10-membered substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl having a 3- to 10-membered ring, and alkyl of 1 to 6 carbon atoms. More preferably, R3 and R4 are selected from the group formed by H, methyl, ethyl, hexyl, dodecyl, or hexadecyl. Even more preferably, R3 is H, and R4 is selected from the group formed by H, methyl, ethyl, hexyl, dodecyl, or hexadecyl. According to an even more preferred embodiment, R2 is selected from -OH and -NH2. According to another embodiment of the present invention, R1 is selected from the group formed by H, acetyl, lauroyl, myristoyl, or palmitoyl, and R2 is -NR3R4 or -OR3, where R3 and R4 are independently selected from H, methyl, ethyl, hexyl, dodecyl, and hexadecyl, and preferably R2 is -OH or -NH2. More preferably, R1 is acetyl or palmitoyl, and R2 is -NH2. In a preferred embodiment, the acyl group is attached to the N-terminus of at least one amino acid of the peptide. In one embodiment of the present invention, the peptide is modified to include a side chain protecting group. The side chain protecting group can be one or more of a benzyl-containing or benzyl-based group, a t-butyl-based group, a benzyloxy-carbonyl (Z) group, and an allyloxycarbonyl (alloc) protecting group. The side chain protecting group can be derived from an achiral amino acid, such as achiral glycine. The use of an achiral amino acid helps stabilize the resulting peptide and also facilitates the facile synthetic route of the present invention. Preferably, the peptide further includes a modified C-terminus, preferably an amidated C-terminus. The achiral residue can be α-aminoisobutyric acid (methylalanine). It will be understood that the specific side chain protecting group used will depend on the peptide sequence and the type of N-terminal protecting group used.

[0170] "Conjugate": In one embodiment of the present invention, the peptide is conjugated, linked, or fused to a binding partner, e.g., one or more polyethylene glycol polymers or other compounds, such as molecular weight-enhancing compounds or lipophilic groups. The molecular weight-enhancing compound is any compound that increases the molecular weight of the resulting conjugate, typically by 10% to 90% or 20% to 50%, and may have a molecular weight between 200 and 20,000, preferably between 500 and 10,000. The molecular weight-enhancing compound may be PEG, any water-soluble (amphiphilic or hydrophilic) polymer moiety, PEG homo- or copolymers, monomethyl-substituted polymers of PEG (mPEG), and polyoxyethyleneglycerol (POG), polyamino acids such as polylysine, polyglutamic acid, polyaspartic acid, especially those in the L-conformation, pharmacologically inactive proteins such as albumin, gelatin, fatty acids, polysaccharides, lipid amino acids, and dextran. The polymeric moiety can be linear or branched and can have a molecular weight of 500 to 40,000 Da, 5,000 to 10,000 Da, or 10,000 to 5,000 Da. The compound (binding partner) can be any suitable cell-permeable compound, such as tat peptide, penetratin, or pep-1. The compound (binding partner) can be an antibody molecule. The compound (binding partner) can be a lipophilic moiety or a polymeric moiety. Lipophilic and polymeric substituents are known in the art. Lipophilic substituents include N, O, or S atoms that form part of an acyl group, sulfonyl group, ester, sulfonyl ester, thioester, amide, or sulfonamide. The lipophilic moiety can include a hydrocarbon chain having 4 to 30 C atoms, preferably between 8 and 12 C atoms. It can be linear or branched, saturated or unsaturated. The hydrocarbon chain can be further substituted. It can be a cycloalkane or heterocycloalkane. The peptides may be modified at the N-terminus, C-terminus, or both. The polymer or compound (binding partner) is preferably linked to an amino, carboxyl, or thio group, and may be linked by the N-terminus or C-terminus of the side chain of any amino acid residue.The polymer or compound (binding partner) can be conjugated to the side chain of any suitable residue. The polymer or compound (binding partner) can be conjugated via a spacer. The spacer can be a natural or unnatural amino acid, succinic acid, lysyl, glutamyl, asparagyl, glycyl, β-alanyl, or γ-aminobutanoyl. The polymer or compound (binding partner) can be conjugated via an ester, sulfonyl ester, thioester, amide, carbamate, urea, or sulfonamide. Those skilled in the art will be aware of suitable means for preparing the described conjugates.

[0171] The term "naturally occurring" as applied to a biologically active (i.e., glucose transport-facilitating) peptide refers to a peptide comprising (a) a biologically active (i.e., glucose transport-facilitating) fragment of a plant protein, typically a rice or pea protein or a variant of a pea protein, including lentil, sweet pea, or chickpea, or a variant of a rice protein, including oat, grass, corn, wild rice, and banana, or (b) a fragment of a plant protein, e.g., a biologically active (i.e., glucose transport-facilitating) variant of a biologically active (i.e., glucose transport-facilitating) fragment of a homolog of a plant protein. The peptides or fragments of the invention can be isolated from plant proteins or can be synthetically produced using methods known to those of skill in the art and described herein.

[0172] "C-terminal domain" as applied to a fragment means the first three amino acids at the c-terminus of the fragment.

[0173] "N-terminal domain" as applied to a fragment means the last three amino acids at the N-terminus of the fragment.

[0174] "Bioactive" as applied to a peptide or fragment means having biological activity when administered to a mammal. The biological activity can be a health-promoting activity. Examples of biological activity include glucose transport promoting, antibacterial, anti-inflammatory, or cell growth or proliferation promoting. In one embodiment, the term "biologically active" refers to glucose transport promoting.

[0175] "Glucose transport-enhancing" or "glucose transport-enhancing activity" as applied to a peptide or fragment means a peptide or fragment that, when used at a concentration of 2 μM in the in vitro assay described below, is capable of increasing GLUT4 translocation into skeletal muscle compared to an untreated control. Preferably, the peptide or fragment is capable of increasing GLUT4 translocation by at least 50% (i.e., a 1% to 1.5% relative unit increase in GLUT4 translocation) compared to an untreated control.

[0176] "Antibacterial" or "antibacterial activity" as applied to a peptide or fragment means a peptide or fragment capable of visibly inhibiting bacterial growth in the following agar plate-based growth inhibition assay: peptide stock = 5 mg / mL dissolved in DMSO. Bacterial inoculum was adjusted to a McFarland 0.5 standard and plated on MHA plates. A blank disc was placed on the plate, and 10 μl of each compound (64 μg / mL - the highest concentration tested) was added. Plates were incubated at 37°C for 16-18 hours. Appropriate controls (DMSO; Mueller-Hinton medium alone; and two antibiotic discs - ciprofloxacin and tetracycline) were also performed.

[0177] "Anti-inflammatory" as applied to a peptide or fragment means a peptide or fragment that is capable of significantly reducing TNFα secretion by LPS-stimulated J774.2 macrophages (compared to untreated LPS-stimulated J774.2 macrophages) when the macrophages are treated with 100 μM of the peptide or fragment. J774.2 macrophages were treated with 100 μM of synthetic peptide for 24 hours and then stimulated with (A) LPS (10 ng / ml) for 5 hours or (B) LPS (10 ng / ml) for 5 hours followed by ATP (5 mM) for 1 hour. Supernatants were collected, and TNFα levels were determined by ELISA.

[0178] "Cell growth or proliferation promotion" as applied to a peptide or fragment refers to a peptide or fragment capable of increasing elastin production or cell proliferation in human skin treated with a 20 μM solution of the peptide or fragment in the following assay. Skin grafts were prepared from abdominoplasty surgeries. Some grafts were degreased with alcohol to obtain dehydrated skin. These grafts were maintained in maintenance medium provided by the supplier Biopredic International for 5 days. The test item was applied twice per day at 5 μL per graft. At the end of the study, two grafts were used as viability controls using MTT, and a third graft was fixed in 4% formaldehyde for histology and cell staining. At each analysis (D1 and D5), histology was performed on the degreased grafts, the test item, the DMSO 0.3% control, and the water control-treated grafts. Each skin graft in maintenance medium was degreased with 5 μL of alcohol for 3 hours after receipt in the laboratory. After 3 hours, all skin grafts were treated with the test items twice per day and incubated at 37°C ± 2°C, 5% CO2 for 1 or 5 days. System integrity was confirmed on days 1 and 5 using a viability control with MTT. Histology was performed by the Gredeco laboratory, and immunostaining for elastin and Ki67 was performed by the same laboratory. Immunostaining for filaggrin was performed by the Intertek laboratory. Detection of elastin (rabbit monoclonal antibody, clone PI5502, LSBio) was performed using a two-layer immunoperoxidase technique (ABC kit, Vector Laboratories) and demonstrated with AEC (3-amino-9-ethylcarbazole). The immunohistochemical staining intensity in elastic fibers was evaluated using a semiquantitative histological score. Epithelial proliferation was analyzed by immunohistochemistry using an anti-Ki67 antibody. Immunodetection was performed using the indirect immunoperoxidase technique, followed by amplification (DAKO kit) and detection with AEC (3-amino-9-ethylcarbazole). Counting of the number of labeled cells (keratinocytes in the basal layer of the epidermis) was performed, providing the total number of basal cells, and the % of labeled cells was calculated.Specific staining for filaggrin is performed using immunoperoxidase staining (ABC kit, Fisher). The intensity of the immunohistochemical marker in the epidermis is evaluated relative to the solvent negative control (water or DMSO 0.3%).

[0179] "Enriched in peptides having a molecular weight of less than 10 KD" as applied to the compositions of the present 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 polypeptides / proteins in the composition having a molecular weight of 10 KD or more.

[0180] A "homologue" of a reference protein should be understood to mean a protein from a different species of plant that has at least 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence homology with the reference protein. Thus, for example, homologues of the pea protein P13918 include: >gi|137584|sp|P08438.1|VCL_VICFA RecName:Full=Vicilin;Flags:Precursor[Vicia faba] >gi|22057|emb|CAA68559.1|Vicilin [Vicia faba var. minor]>gi|383931031|gb|AFH56916.1|Vicilin [Vicia faba] >gi|502105533|ref|XP_004492829.1|PREDICTED:Vicilin-like isoform X1 [Chickpea] Chickpea >gi|29539109|emb|CAD87730.1|Allergen Len c1.0101 [Lentil] Lentil Includes:

[0181] A "variant" of a biologically active (i.e., glucose transport-enhancing) fragment should be taken to mean a fragment having an amino acid sequence substantially identical to the reference biologically active (i.e., glucose transport-enhancing) fragment and having the relevant biological activity (i.e., glucose transport-enhancing activity) as defined above. Thus, for example, the term should be taken to include fragments in which one or more amino acid residues are altered. Preferably, such alterations include insertions, additions, deletions, and / or substitutions of five or fewer amino acids, more preferably four or fewer, even more preferably three or fewer, and most preferably only one or two amino acids. Insertions, additions, and substitutions using natural and modified amino acids are contemplated. Variants may have conservative amino acid changes, in which the introduced amino acid is structurally, chemically, or functionally similar to that substituted. In one embodiment, one or more L-amino acids are substituted with D-amino acids. Generally, a variant will have at least 70% amino acid sequence identity with a reference glucose transport-promoting fragment, preferably at least 80%, more preferably at least 90%, and ideally at least 95%, 96%, 97%, 98%, or 99% sequence identity. As used herein, the term "sequence identity" should be understood to encompass both sequence identity and similarity; that is, a variant (or homolog) that shares 70% sequence identity with a reference sequence will have any 70% of the aligned residues of the variant (or homolog) identical to or conservatively substituted for the corresponding residues in the reference sequence over the entire length of the sequence. Sequence identity is the amount of exactly corresponding characters between two different sequences. Consequently, gaps are not counted, and the measurement is relative to the shorter of the two sequences. With respect to "sequence homology," this term should be understood to mean a variant (or homolog) that shares a defined percentage of similarity or identity with a reference sequence, where a percentage of aligned residues of the variant (or homolog) are either identical to or conservative substitutions of corresponding residues in the reference sequence, and the variant (or homolog) shares the same function as the reference sequence.This alignment and 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.

[0182] Variants of SEQ ID NO:7, including variants with 1, 2 or 3 conservative amino acid substitutions, 1, 2 to 3 non-conservative amino acid substitutions, 1-2 amino acid additions, 1, 2 or 3 amino acid deletions, are provided below: One conservative amino acid substitution: ILDLAIPVNRPGQL (SEQ ID NO: 85); VLELAIPVNRPGQL (SEQ ID NO: 86); VLDLAVPVNRPGQL (SEQ ID NO: 87); VLDLAIPINRPGQL (SEQ ID NO: 88); VLDLAIPVNKPGQL (SEQ ID NO: 89); VLDLAIPVEKPGQL (SEQ ID NO: 90); VLDLAIPVNKPGEL (SEQ ID NO: 91) Two conservative amino acid substitutions: ILELAIPVNRPGQL (SEQ ID NO: 92); ILDLAVPVNRPGQL (SEQ ID NO: 93); VLELAVPVNRPGQL (SEQ ID NO: 94); VLELAIPVNKPGQL (SEQ ID NO: 95); ILDLAIPVNKPGQL (SEQ ID NO: 96); VLDLAVPVNKPGQL (SEQ ID NO: 97); VLDLAIPVEKPGEL (SEQ ID NO: 98); ILDLAIPVNKPGEL (SEQ ID NO: 99); VLELAIPVEKPGQL (SEQ ID NO: 100).

[0183] Three conservative amino acid substitutions: ILELAVPVNRPGQL (SEQ ID NO: 101);ILELAIPVNKPGQL (SEQ ID NO: 102); VLELAVPVNKPGQL (SEQ ID NO: 103);ILELAIPVNRPGEL (SEQ ID NO: 104); ILDLAIPVNKPGEL (SEQ ID NO: 105); VLDLAVPVEKPGQL (SEQ ID NO: 106); VLDLAVPVERPGEL (SEQ ID NO: 107); VLELAIPVERPGEL (SEQ ID NO: 108).

[0184] One non-conservative amino acid substitution KLDLAIIVNRPGQL (SEQ ID NO: 109); VLDLAIPVNRPGQK (SEQ ID NO: 110); VLDLAIPVNRPGQL (SEQ ID NO: 111); VLDLAIPVNRPGQL (SEQ ID NO: 112); VLDLAIPVNRPCQL (SEQ ID NO: 113); VLDLWIPVNRPGQL (SEQ ID NO: 114); VLDLAIPVNRPGQL (SEQ ID NO: 115); VLYLAIPVNRPGQL (SEQ ID NO: 116).

[0185] Two non-conservative amino acid substitutions VLDLYIPVGRPGQL (SEQ ID NO: 117); VKDLAIPWNRPGQL (SEQ ID NO: 118); VLDLAIPVNRPCCL (SEQ ID NO: 119); VLDLAGGVNRPGQL (SEQ ID NO: 120); VLDLAIPKNEPGQL (SEQ ID NO: 121); PLDLAIPVNDPGQL (SEQ ID NO: 122); VLDLAIPVNRPIQL (SEQ ID NO: 123); VLDHAIPVNRPGQL (SEQ ID NO: 124) Three non-conservative amino acid substitutions VLDLAIPVNRPGGG (SEQ ID NO: 125); VLDLHIPGNEPGQL (SEQ ID NO: 126); VYKLAIPVNEPGQL (SEQ ID NO: 127); VLDLAIPVNRPYPG (SEQ ID NO: 128); VLDYAIPKNDPGQL (SEQ ID NO: 129); VLDLAIPVNRPGQL (SEQ ID NO: 130); RRRLAIPVNRPGQL (SEQ ID NO: 131); VLDLAIGVNRGPQL (SEQ ID NO: 132) Addition of one or two amino acids VLDLAIPVNRPGFQL (SEQ ID NO: 133); VLDLADIPVNRPGQL (SEQ ID NO: 134); VLDLAIPVGNRPGQL (SEQ ID NO: 135); VLQQDLAIPVNRPGQL (SEQ ID NO: 136); VLDLAIPVNRGPGQKL (SEQ ID NO: 137); VLDGLPLAIPVNRPGQL (SEQ ID NO: 138); VLDLAIPVNRPGQLLL (SEQ ID NO: 139); VLDLFLGAIPVNRPGQL (SEQ ID NO: 140) One, two, or three amino acid deletions VLDLAIPVNRGQL (SEQ ID NO: 141); VLDLAPVNRPGQL (SEQ ID NO: 142); LDLAIPVNRPGQL (SEQ ID NO: 143); VLDLAIPVNRPGQ (SEQ ID NO: 144); DLAIPVNRPGQL (SEQ ID NO: 145); VLDLAIPVNRPG (SEQ ID NO: 146); VLDLAINRPGQL (SEQ ID NO: 147); VLDAIVNPGQL (SEQ ID NO: 148) Variants of SEQ ID NO:8 include SEQ ID NO:7 (three deletions), SEQ ID NO:14 (one amino acid deletion), and SEQ ID NO:15 (one addition). Variants of SEQ ID NO:9 include SEQ ID NO:13 (one addition) and SEQ ID NO:11 (three amino acid addition). Variants of SEQ ID NO:10 include SEQ ID NOs:158 and 161. Variants of SEQ ID NO:11 include SEQ ID NOs:9 and 13. Variants of SEQ ID NO:12 include SEQ ID NOs:8 and 16. Variants of SEQ ID NO:13 include SEQ ID NOs:9 and 11. Variants of SEQ ID NO:14 include SEQ ID NOs:10 and 15. Variants of SEQ ID NO:15 include SEQ ID NOs:7, 8, 12, and 14. Variants of SEQ ID NO:16 include SEQ ID NO:12. Variants of SEQ ID NO:17 include SEQ ID NOs:12 and 13. Variants of SEQ ID NO:18 include SEQ ID NO:19. Variants of SEQ ID NO:19 include SEQ ID NO:18.

[0186] The term "variant" should be taken to include fragments of the peptides of the invention. Typically, fragments have a length of between 8 and 23 consecutive amino acids. Generally, fragments have a charge of -5 to +3. Optionally, fragments include a C-terminal amino acid that is not C, I, K, M, P, T, or W. Optionally, fragments typically have an N-terminal amino acid that is not C, D, H, M, P, T, V, or W. The charge of a peptide fragment or region is determined using the method of

[16] .

[0187] "Fragments of peptides" or "peptide fragments" of the invention can 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 have biological activity, such as anti-inflammatory activity, anti-aging activity, glucose transport promoting activity, or antibacterial activity. In one embodiment, 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 (sequence number 149); VLDLAIPVNRPG (sequence number 150); VLDLAIPVNRP (sequence number 151); LDLLAIPVNRPGQL (sequence number 152); DLAIPVNRPGQL (sequence number 153); LAIPVNRPGQL (sequence number 154); LDLLAIPVNRPGQ (sequence number 155); DLAIPVNRPG (sequence number 156); LAIPVNRP (sequence number 157); VLDLAIPVN (sequence number 158); AIPVNRPGQL (sequence number 159); VNRPGQL (sequence number 160); VLDLAIPV (sequence number 161), and VLDLAIPVNR (sequence number 10).

[0188] Pharmaceutical Composition: A further aspect of the present invention relates to a pharmaceutical composition comprising a peptide of the present invention or a composition of peptides of the present invention mixed with one or more pharmaceutically acceptable diluents, excipients, or carriers. While the peptides and compositions of the present invention can be administered alone, they are generally administered in admixture with a pharmaceutical carrier, excipient, or diluent, particularly for human therapy. The pharmaceutical composition may be for human and animal use in human and veterinary medicine. Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein can be found in Non-Patent Document 11. In particular, topical delivery formulations are described in Non-Patent Document 12, the entire contents of which are incorporated herein by reference. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts and are described, for example, in Non-Patent Document 13. Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Examples of suitable diluents include ethanol, glycerol, and water. The choice of pharmaceutical carrier, excipient, or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions can contain any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s) as, or in addition to, the carrier, excipient, or diluent. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flowing lactose, β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Preservatives, stabilizers, dyes, and even flavoring agents can be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0189] The peptides or compositions of the present invention may be adapted for topical, oral, rectal, parenteral, intramuscular, intraperitoneal, intraarterial, intrabronchial, subcutaneous, intradermal, intravenous, intranasal, vaginal, buccal, or sublingual administration. For oral administration, compressed tablets, pills, tablets, gels, drops, and capsules are particularly used. Preferably, these compositions contain 1 to 250 mg, more preferably 10-100 mg, of active ingredient per dose. Other forms of administration include solutions or emulsions that may be injected intravenously, intraarterially, subcutaneously, intradermally, intraperitoneally, or intramuscularly and are prepared from sterile or sterilizable solutions. Pharmaceutical compositions of the present invention may be in the form of suppositories, vaginal rings, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions, or dusting powders. The compositions of the present invention may be formulated for topical delivery. Topical delivery generally refers to delivery to the skin, but can also refer to delivery to epithelial-lined body cavities, such as the lungs or respiratory tract, the gastrointestinal tract, and the buccal cavity. In particular, topical delivery formulations are described in Non-Patent Document 12, the entire contents of which are incorporated herein by reference. Compositions or formulations for delivery to the respiratory tract are described in Non-Patent Document 14, Patent Document 13, Patent Document 14, Patent Document 15, and Patent Document 16. Compositions and formulations for delivering active agents to the ileum, particularly the proximal ileum, include microparticles and microencapsulations in which the active agent is encapsulated within a protective matrix formed from polymers or milk proteins that are acid-resistant but tend to dissolve in the more alkaline environment of the ileum. Examples of such delivery systems are described in Patent Documents 17 and 18. An alternative to transdermal administration is through the use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol 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 stabilizers and preservatives as may be required.

[0190] Injectable forms may contain between 10 and 1000 mg, preferably between 10 and 250 mg, of active ingredient per dose.

[0191] Compositions may be formulated in unit dosage form, ie, in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.

[0192] Those skilled in the art can easily determine the appropriate dosage of one of the compositions to be administered to a subject without undue experimentation. Typically, a physician will determine the actual dosage most suitable for an individual patient, which will depend on various factors, including the activity of the particular compound, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combinations, the severity of the individual's condition, and the therapy the individual is currently receiving. The dosages disclosed herein are exemplary of average cases. Of course, there may be individual cases where higher or lower dosage ranges are warranted, and such are within the scope of the present invention. If necessary, the agent may be administered at a dose of 0.1 to 10 mg / kg, more preferably 0.01 to 30 mg / kg, such as 0.1 to 1 mg / kg body weight. In an exemplary embodiment, one or more doses of 10 to 300 mg / day, or more preferably 10 to 150 mg / day, are administered to the patient.

[0193] In a particularly preferred embodiment, the methods and uses of the present invention include administering the peptide or composition of the present invention in combination with one or more other active agents, such as existing glucose transport-enhancing drugs or pharmacological enhancers available on the market. In such cases, the compound of the present invention can be administered continuously, simultaneously, or sequentially with one or more other active agents.

[0194] In one embodiment of the present invention, the peptide of the present invention can be administered in the form of a conjugate comprising the peptide, and optionally 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. In one embodiment, the peptide can be modified to replace one or more amino acids with amino acids used to attach to the partner molecule. For example, an amino acid can be replaced with a lysine residue for the purpose of conjugating a partner molecule such as a PEG molecule.

[0195] "Artificial" as applied to edible products shall be understood to mean produced by the hand of man and not occurring in nature.

[0196] "Improving muscle condition" means improving muscle health, for example, promoting skeletal muscle protein synthesis, skeletal glucose uptake, improving lean tissue mass in a therapeutic or non-therapeutic setting, promoting muscle recovery generally after vigorous exercise, or improving muscle performance. The method or use may be therapeutic or non-therapeutic. The term "improving lean tissue mass condition" should be understood to mean increasing lean tissue mass or inhibiting or preventing the rate of lean tissue mass breakdown.

[0197] "Promoting muscle recovery" means causing an increase in glucose uptake in skeletal muscle compared to untreated skeletal muscle.

[0198] "Disease or condition characterized by lethargy or low energy levels" means any condition or disease characterized by feelings of fatigue or low energy. Examples include allergies, asthma, anemia, cancer and its treatment, chronic pain, heart disease, infection, depression, eating disorders, grief, sleep disorders, thyroid problems, medication side effects, alcohol use, or drug use.

[0199] "Maintaining or restoring muscle health" means helping to maintain or restore muscle health in a mammal resulting from damage sustained during exercise. By promoting glucose transport in skeletal muscles, the peptides promote recovery from exercise and reduce muscle soreness and injury associated with exercise. They can also be used to reduce and prevent muscle cramps, allowing for faster recovery from muscle cramps. Cramps can be caused by physical stress, mental stress, and / or repetitive strain trauma stress. By promoting glucose transport, the peptides help to reduce muscle myopathy, help prevent sarcopenia in mammals, promote recovery from exercise injuries, and reduce muscle soreness and injury associated with exercise. The present invention also relates to a peptide or composition of the present invention for use in maintaining or restoring muscle health in a mammal.

[0200] "Metabolic disorders characterized by dysregulated glucose or insulin levels in mammals" should be understood to include prediabetes, diabetes, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, diabetic dyslipidemia, hyperlipidemia, hypertension, hypertriglyceridemia, hyperfattyacidemia, hypercholerolemia, hyperinsulinemia, MODY and HNF1A-MODY.

[0201] "Improved glycemic control" should be understood to mean one or more of lowering plasma blood glucose levels, in particular postprandial blood glucose levels, treating or preventing hyperglycemia, increasing postprandial insulin secretion, regulating glucose homeostasis and reducing or attenuating insulin resistance. [Brief explanation of the drawings]

[0202] [Figure 1A] FIG. 1 shows the effect of synthetic peptide SEQ ID NO: 51 (rice) on glucose uptake in skeletal muscle cells. [Figure 1B]FIG. 1 shows the effect of synthetic peptide SEQ ID NO: 13 (pea) on glucose uptake in skeletal muscle cells. [Figure 2] FIG. 1 shows the effect of synthetic peptide SEQ ID NO: 66 (rice) on glucose uptake in skeletal muscle cells. [Figure 3] FIG. 1 shows the effect of synthetic peptide SEQ ID NO: 7 (rice) on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells. [Figure 4] FIG. 1 shows the effect of peptide composition E_1_BE on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells. [Figure 5] FIG. 1 shows the effect of peptide composition I_2_BE on GLUT4 translocation in L6-GLUT4myc skeletal muscle cells. DETAILED DESCRIPTION OF THE INVENTION

[0203] Detailed Description of the Invention [Example]

[0204] Measuring glucose uptake using 2-deoxyglucose (2-DG) is a widely accepted method used to examine glucose uptake in skeletal muscle cells. 2-DG is taken up by glucose transporters and metabolized to 2-DG-6-phosphate (2-DG6P). The amount of unmetabolized 2-DG6P that accumulates is proportional to glucose uptake by the cells.

[0205] method: 1. Human skeletal osteoblasts (Sigma 150-05a) were seeded in 96-well plates at 10,000 cells per well in skeletal muscle differentiation medium and allowed to differentiate for 72 hours prior to the experiment.

[0206] 2. Differentiated cells were serum-starved for 24 hours and then stimulated with insulin or synthetic peptides. After starvation, the serum-free medium was removed, cells were rinsed with phosphate-buffered saline (PBS), and the medium was replaced with 100 μl of Krebs-Ringer-Phosphate-HEPES (KRPH) and incubated for 1 hour.

[0207] 3. Cells were then stimulated with 100 nM insulin for 30 minutes or with 5 μg / ml, 0.5 μg / ml or 0.05 μg / ml synthetic peptides for 3 hours, respectively.

[0208] 4. After stimulation, cells were incubated with 10 μl / well of 2-DG solution for 40 min, and glucose uptake was measured using the “PrismColor Glucose Uptake Assay Kit” (Molecutools), and all steps were performed according to the manufacturer's instructions.

[0209] 5. Results were calculated as a percentage of the untreated control. An increase in optical density reading indicates greater uptake of 2-DG6P and increased glucose uptake.

[0210] All experiments were performed in duplicate on triplicate plates (6 wells / condition). Significance was determined using Student's t-test (*p<0.05 compared to control, **p<0.01 compared to control, ***p<0.001 compared to control).

[0211] The results are shown in Figures 1 and 2 - all synthetic peptides caused a significant increase in glucose uptake in the cells. [Example]

[0212] Study Description Skeletal muscle is the primary site of glucose disposal (80%) under insulin-stimulated or postprandial conditions. Under these conditions, glucose transport into skeletal muscle is primarily facilitated by the insulin-responsive glucose transport protein GLUT4, which translocates to the cell surface upon insulin or contractile stimulation.

[0213] We determined the effects of six synthetic peptides (SP1–6) and four peptide compositions on in vitro GLUT4 translocation using the L6 rat skeletal muscle cell line. Using a clone of the L6 cell line containing overexpression of c-myc epitope-tagged GLUT4 (kindly provided by Prof. Amira Klip, Hospital for Sick Children, Toronto), the efficacy of each synthetic peptide and peptide composition on GLUT4 translocation was examined in a dose-response design.

[0214] SP2 [SEQ ID NO: 7] is a glucose transport-facilitating fragment of the pea protein P13918, while peptides SP1 and SP3-SP6 are comparison peptides.

[0215] SP1(E_685two_BE) DTFYNAAWDPSNR [SEQ ID NO: 85] SP2(E_64two_BE) VLDLAIPVNRPGQL [SEQ ID NO: 7] SP3(E_93_BE) YQHQQGGKQEQENEGNNIFSGFK [SEQ ID NO: 86] SP4(I_641_BE) ALDWAIANLLR [SEQ ID NO: 87] SP5(I_1021_BE) YDYENVDAGAAK [SEQ ID NO: 88] SP6(I_24_BE) EVQDSPLDACR [SEQ ID NO: 89] The following peptide compositions were tested in an in-vitro assay for skeletal muscle glucose transport activity.

[0216] I_2_BE (containing peptides of SEQ ID NOs: 7 and 10) E_1_BE (containing peptides of SEQ ID NOs: 48, 49, 50, 51, 54, 58, 60, 61, 62, and 63)

[0217] cell culture L6-GLUT4myc cells were grown in 10% FBS and 2 μg / ml blasticidin. Cells were grown for 48–72 hours, then seeded at 15,000 cells per well in 2% FBS in 24-well plates and allowed to differentiate for 6–8 days prior to experimentation.

[0218] L6-GLUT4myc cells were serum-starved for 3 hours and then incubated with 100 nM insulin for 30 minutes or with 200, 20, 2.0, and 0.2 μM SP and 2, 1, 0.5, and 0.25 mg / ml peptide compositions for 3 hours. The 3-hour incubation period was chosen based on previous findings identifying that 3 hours of incubation with branched-chain amino acid containing dipeptides increases glucose uptake in L6 myotubes. Treatments were staggered to determine GLUT4myc translocation at the same time point.

[0219] Measurement of GLUT4myc translocation in L6 myotubes The amount of myc-tagged GLUT4 on the cell surface was measured using an antibody-coupled colorimetric assay. Briefly, after incubation with either insulin for 30 minutes or synthetic peptides or peptide compositions for 3 hours, L6-GLUT4myc cells were fixed by incubation with 3% paraformaldehyde (PFA). The PFA was then quenched by adding 0.1 M glycine solution, and the cells were blocked with 5% goat serum. Myotube monolayers were exposed to anti-myc antibodies and then incubated with peroxidase-conjugated donkey anti-mouse IgG. One mL of o-phenylenediamine dihydrochloride (OPD) reagent was added to each well, and the reaction was stopped by adding 250 μl / well of 3 M HCl. To determine GLUT4 translocation to the cell surface, aliquots from each condition were examined spectrophotometrically in a plate reader using absorbance at 492 nm.

[0220] Synthetic peptides Peptides were first diluted in a suitable solvent. Dimethyl sulfoxide (DMSO) was the solvent of choice for peptides with predicted low aqueous solubility. The final concentrations of DMSO in each well are shown in Table 1: 200, 20, 2, and 0.2 μM for each synthetic peptide.

[0221] Peptide Composition Peptide compositions were prepared by adjusting the pH to between 6 and 7 using 1 M NaOH or HCl, followed by sterile filtration.

[0222] [Table 1]

[0223] Synthetic peptides In addition to the untreated control, 100 nM insulin was used to stimulate the maximum GLUT4 translocation response, i.e., the positive control in each experiment. The average increase in cell surface GLUT4 translocation in response to 100 nM insulin was 1.72-fold compared to the untreated control (Figure 3). Treatments were staggered so that all conditions (untreated, insulin, and sample) were treated at the same time point. At concentrations ranging from 0.2 to 2 μM, SP2 tended to increase GLUT4 translocation. SP1 at 200 μM tended to decrease translocation due to poor cell viability.

[0224] Peptide Composition Peptide composition E_1_BE tended to increase GLUT4 translocation at concentrations ranging from 0.25 to 0.5 mg / ml, but 1 and 2 mg / ml induced progressive cell death.

[0225] Furthermore, composition I_2_BE tended to increase GLUT4 translocation in a dose-dependent manner (Figures 4-6).

[0226] Experimental Conclusion SP2 and compositions E_1_BE and I_2_BE showed a trend toward a stimulatory effect on skeletal muscle GLUT4 translocation, warranting further investigation into their ability to promote glucose transport in skeletal muscle. [Example]

[0227] Antihyperglycemic properties of peptide compositions I2BE and E1BE in db / db mice

[0228] preparation I_2_BE or E_1_BE is administered as a solution or suspension in purified water. Stability data indicate that a 10 mg / ml test article formulation in purified water is stable for 10 hours at +2 to +8°C protected from light. Therefore, the test article formulation should be kept at +2 to +8°C protected from light and used within 10 hours of preparation. Formulation characteristics and maximum storage periods are detailed below.

[0229] material Species: Mouse Strain: BKS.Cg-Dock7m+ / +Leprdb / J (db / db diabetic mice) (souche JAX™ mouse strain). Species Selection: The mouse was chosen due to its acceptability as a predictor of the pharmacological effects of drugs in humans and the recognition by regulatory agencies that this species is suitable for pharmacodynamic studies.

[0230] Age: 8-9 weeks on the day of randomization Body weight: On the day of randomization, a maximum range of 2.5 g must be achieved between each group. Animal weights on the day of randomization will be noted in the report. Approximately 10% excess animals will be ordered to allow for sorting of animals based on weight; if not assigned to a group, these will be available as reserve animals in case of unforeseen events.

[0231] Study design The study included three groups of 12 animals each. The groups were as follows: Group 1: Control group administered with vehicle (purified water) Group 2: 100 mg / kg I2BE, po Group 3: 100 mg / kg E_1_BE, po

[0232] Treatment assignment for each animal is randomized prior to the start of the study, and group homogeneity is confirmed by body weight and glycemic criteria measured on the day of randomization.

[0233] Justification for number of animals per group: The number of animals per group is the minimum that allows for accurate assessment of the pharmacokinetic profile.

[0234] Research Calendar D-4: Animal weight measurement, glycemia measurement, enrollment and randomization D1: Animal weight measurement, start of daily oral administration of test item or vehicle, and glycemia measurement D8: Animal weight and glycemia measurements D15: Animal weight and glycemia measurements Days 16-18: Oral glucose tolerance test (OGTT) D22: Animal weight and glycemia measurements D29: Animal weight and glycemia measurements Days 29-31: Blood sampling followed by organ sampling

[0235] Glycemic control Blood glucose levels are measured weekly 90±30 minutes after each daily treatment, from D1 up to D29. A drop of blood is collected from the tail vein of a non-fasting db / db mouse, placed on the tip of a glucose strip (Nova Biomedical), and placed in a glucose meter (Nova Biomedical).

[0236] Oral glucose tolerance test (OGTT) Over the third week (D16-D18), an OGTT was performed after an overnight fasting period. After blood glucose measurements (pre-dose), 30 min after the daily oral administration of the test item or vehicle, the animals were dosed orally with 10 mL / kg of a 0.2 g / mL (2 g / kg) glucose solution in purified water. Blood glucose levels were then measured 15, 30, 60, 90, and 120 min after glucose overload, following the same procedure as above.

[0237] Interim Results The effects of I_2_BE and E_1_BE on body weight and glycemia are compared with those of the vehicle, and the delta corresponding to the glycemic evolution in each group from D1 to D15 is calculated. The evolution of blood glucose from D-5 to D1, and therefore before treatment, shows that the disease progression is the same in all three groups. A strong trend of activity was observed for both peptide compositions compared to the control between D1 and D15, indicating that both peptide compositions can control the glycemic evolution in diabetic animals.

[0238] result The effects of I_2_BE and E_1_BE on body weight and glycemia are compared to those of vehicle using analysis of variance for repeated measures with Dunnett's test if significant (P≦0.05). For OGTT, glycemia results after glucose overload in treated animals are compared to those of vehicle animals using analysis of variance for repeated measures with Dunnett's test if significant (P=0.05). Biochemistry results (plasma glucose, HbAlc, and insulin) are expressed as absolute values. The effects of I_2_BE and E_1_BE on biochemical parameters are compared to those of vehicle using analysis of variance with Dunnett's test if significant (P≦0.05).

[0239] Sequence information

[0240] Protein: P13918 - 1 - Pea MAATTMKASFPLLMGISFLASVCVSSRSDPQNPFIFKSNKFQTLFENENGHIRLLQKFDQRSKIFENLQNYRLEYKSKPHTIFLPQHTDADYILVVLSGKAILTVLKPDDR NSFNLERGDTIKLPAGTIAYLVNRDDNEELRVLDLAIPVNRPGQLQSFLLSGNQNQQNYLSGFSKNILEASFNTDYEEIEKVLLEEHEKETQHRRSLKDKRQQSQEENVIVKLSR GQIEELSKNAKSTSKKSVSSESEPFNLRSRGPIYSNEFGKFFEITPEKNPQLQDLDIFVNSVEIKEGSLLLPHYNSRAIVIVTVNEGKGDFELVGQRNENQQEQRKEDDEEEEQG EEEINKQVQNYKAKLSSGDVFVIPAGHPVAVKASSNLDLLGFGINAENNQRNFLAGDEDNVISQIQRPVKELAFPGSAQEVDRILENQKQSHFADAQPQQRERGSRETRDRLSSV [SEQ ID 1]

[0241] Peptide: VLDLAIPVNRPGQL [SEQ ID 7] Peptide: VLDLAIPVNRPGQLQSF [SEQ ID 8] Peptide: SFLLSGNQNQQNYLS [SEQ ID 9] Peptide: VLDLAIPVNR [SEQ ID 10] Peptide: SFLLSGNQNQQNYLSGFS [SEQ ID 11] Peptide: LAIPVNRPGQLQSFLLSG [SEQ ID 12] Peptide: SFLLSGNQNQQNYLSG [SEQ ID 13] Peptide: LDLAIPVNRPGQL [SEQ ID 14] Peptide: VLDLAIPVNRPGQLQ [SEQ ID 15] Peptide: LAIPVNRPGQLQSFLLSGNQNQ [SEQ ID 16] Peptide: SFLLSGNQNQQNYLSGFSKNILE [SEQ ID 17] Peptide: GSLLLPHYN [SEQ ID 18] Peptide: GSLLLPHYNS [SEQ ID 19] Peptide: SSNLDLLGFG [SEQ ID 20] Peptide: FLPQHTD [SEQ ID 181] P13918 Peptide: PGQLQSFLLSGNQNQQNYLSGF [SEQ ID 190] P13918 Peptide: QLQSFLLSGNQNQQNYLSGFSK [SEQ ID 191] P13918 Peptide: QSFLLSGNQNQQ [SEQ ID 192] P13918 Peptide: PGQLQSFLLSGN [SEQ ID 193] P13918 Peptide: QSFLLSGNQ [SEQ ID 194] P13918 Peptide: QNQQNYLSGFSK [SEQ ID 195] P13918 Peptide: PGQLQSFLLSGNQNQQNYLSGFSK [SEQ ID 204] P13918 Peptide: SKPHTIFLPQHTDADYILVVLSGK [SEQ ID 207] P13918 Peptide: VLDLAIPVNRPGQLQSFLLSGNQNQQNYLSGFSK [SEQ ID 216] Peptide: QSFLLSGNQNQQNYLSG [SEQ ID 217] Peptide: RLSSV [SEQ ID 218]

[0242] Protein: Q9M3X6 - 2 - Pea MATTIKSRFPLLLLLGIIFLASVVCVTYANYDEGSEPRVPAQRERGRQEGEKEEKRHGEWRPSYEKEEDEEEGQRERGRQEGEKEEKRHGEWRPSYEKQEDEEEKQKYRYQREKEDEEEKQKYQYQREKKEQKEVQPGRERWEREEDEEQVDE EWRGSQRREDPEERARLRHREERTKRDRRHQREGEEEERSSESQERRNPFLFKSNKFLTLFENENGHIRLLQRFDKRSDLFENLQNYRLVEYRAKPHTIFLPQHIDADLILVVLSGKAILTVLSPNDRNSYNLERGDTIKLPAGTTSYLVNQD DEEDLRLVDLVIPVNGPGKFEAFDLAKNKNQYLRGFSKNILEASYNTRYETIEKVLLEEQEKDRKRRQQGEETDAIVKVSREQIEELKKLAKSSSKKSLPSEFEPINLRSHKPEYSNKFGKLFEITPEKKYPQLQDLDLFVSCVEINEGALML PHYNSRAIVVLLVNEGKGNLELLGLKNEQQEREDRKERNNEVQRYEARLSPGDVVIIPAGHPVAITASSNLNLLGFGINAENNERNFLSGSDDNVISQIENPVKELTFPGSVQEINRLIKNQKQSHFANAEPEQKEQGSQGKRSPLSSILGTFY [SEQ ID 2]

[0243] Peptide: AFDLAKNKNQYLRGFS [SEQ ID 21] Peptide: QYLRGFSKNILE [SEQ ID 22] Peptide: NLLGFGINAE [SEQ ID 23] Peptide: SNLNLLGFG [SEQ ID 24] Peptide: LAKNKNQYLRGFSKN [SEQ ID 25] Peptide: LAKNKNQYLRGFSK [SEQ ID 26] Peptide: LRGFSKNILE [SEQ ID 27] Peptide: YSNKFGKLFE [SEQ ID 28] Peptide: AFDLAKNKNQYLRGF [SEQ ID 29] Peptide: AFDLAKNKNQYLRGFSK [SEQ ID 30] Peptide: NKNQYLRGFS [SEQ ID 31] Peptide: NKNQYLRGFSKNILE [SEQ ID 32] Peptide: SSNLNLLGFG [SEQ ID 33] Peptide: EYSNKFGKLFE [SEQ ID 34] Peptide: ASSNLNLLG [SEQ ID 35] Peptide: LNLLGFGI [SEQ ID 36] Peptide: NKFGKLFE [SEQ ID 37] Peptide: VQPGRERWEREEDEEQVDE [SEQ ID 38] Peptide: RERWEREEDEEQVDE [SEQ ID 39] Peptide: ASSNLNLLGF [SEQ ID 40] Peptide: LAKNKNQYLRGFS [SEQ ID 41] Peptide: ELLGLKNE [SEQ ID 42] Peptide: ASSNLNLL [SEQ ID 43] Peptide: YPQLQDLDL [SEQ ID 44] Peptide: LLGLKNEQQE [SEQ ID 45] Peptide: LVVLSGKAIL [SEQ ID 46] Peptide: LRGFSK [SEQ ID 162] Q9M3X6 Peptide: GALMLPHYN [SEQ ID 163] Q9M3X6 Peptide: GALMLPHYNSR [SEQ ID164 ] Q9M3X6 Peptide: YLRGFS [SEQ ID 196] Q9M3X6 Peptide LVDLVIPVNGPGKFEAFDLAK [SEQ ID 203] Q9M3X6 Peptide: LRGFSKN [SEQ ID 226]

[0244] Protein: Q0DEV5 - 1 - Rice MSALTTSQLATSATGFGIADRSAPSSLLRHGFQGLKPRSPAGDGATSLSVTTSARATPKQQRSVQRGSRRFPSVVVYATGAGMNVVFVGAEMAPWSKTGLGDVLGGLPAMAANGHRVMVISPRYDQYKDAWDTSVVAEIKVADRYERVRF FHCYKRGVDRVFIDHPSFLEKVWGKTGEKIYGPDTGVDYKDNQMRFSLLCQAALEAPRILNLNNNPYFKGTYGEDVVFVCNDWHTGPLASYLKNNYQPNGIYRNAKVAFCIHNISYQGRFAFEDYPELNLSERFRSSFDFIDGYDTPVEGRK INWMCAGILEADRVLTVSPYYAEELISGIARGCELDNIMRLTGITGIVNGMDVSEWDPSKDKYITAKYDATTAIEAKANLKEALQAEAGLPVDRKIPLIAFIGRLEEQKGPDVMAAAIPELMQEDVQIVLLGTGKKKFEKLLKSMEEKYPGK VRAVVKFNAPLAHLIMAGADVLAVPSRFEPCGLIQLQGMRYGTPCACASTGGLVDTVIEGKTGFHMGRLSVDCKVVEPSDVKKVAATLKRAIKVVGTPAYEEMVRNCMNQDLSWKGPAKNWENVLLGLGVAGSAPGIEGDEIAPLAKENVAAP [SEQ ID 3]

[0245] peptide : YDATTAIEAK [SEQ ID 47] peptide :HPSF [SEQ ID 189] Q0DEV5

[0246] protein : P14323 - 2 - イネ MASSVFSRFSIYFCVLLLCHGSMAQLFNPSTNPWHSPRQGSFRECRFDRLQAFEPLRKVRSEAGVTEYFDEKNELFQCTGTFVIRRVIQPQGLLVPRYTNIPGVVYIIQGRGSMGLTFPGCPAT YQQQFQQFSSQGQSQSQKFRDEHQKIHQFRQGDIVALPAGVAHWFYNDGDAPIVAVYVYDVNNNANQLEPRQKEFLLAGNNNRAQQQQVYGSSIEQHSGQNIFSGFGVEMLSEALGINAVAAKRL QSQNDQRGEIIHVKNGLQLLKPTLTQQQEQAQAQDQYQQVQYSERQQTSSRWNGLEENFCTIKVRVNIENPSRADSYNPRAGRITSVNSQKFPILNLIQMSATRVNLYQNAILSPFWNVNAHSLV YMIQGRSRVQVVSNFGKTVFDGVLRPGQLLIIPQHYAVLKKAEREGCQYIAIKTNANAFVSHLAGKNSVFRALPVDVVANAYRISREQARSLKNNRGEEHGAFTPRFQQQYYPGLSNESESETSE [SEQ ID 4]

[0247] Peptide: NGLQLLKPTL [SEQ ID 48] Peptide: GLQLLKPTL [SEQ ID 49] Peptide: GVLRPGQLL [SEQ ID 50] Peptide: DGVLRPGQLL [SEQ ID 51] Peptide: LQLLKPTLTQQQE [SEQ ID 52] Peptide: FLLAGNNNR [SEQ ID 53] Peptide: EFLLAGNNNR [SEQ ID 54] Peptide: FLLAGNNNRAQQQQVYGSSIE [SEQ ID 55] Peptide: FLLAGNNNRAQQQQ [SEQ ID 56] Peptide: FLLAGNNNRAQQQQVYG [SEQ ID 57] Peptide: FLLAGNNNRAQQQQVY [SEQ ID 58] Peptide: FQQQYYPGLSNESESETSE [SEQ ID 59] Peptide: VFDGVLRPG [SEQ ID 165] P14323 Peptide: LQSQND [SEQ ID 166] P14323 Peptide: LQSQNDQRGEI [SEQ ID 167] P14323 Peptide: QSQNDQRGEIIHVK [SEQ ID 168] P14323 Peptide: RGEIIHVK [SEQ ID 169] P14323 Peptide: RLQSQNDQ [SEQ ID 170] P14323 Peptide: RLQSQNDQRG [SEQ ID 171] P14323 Peptide: RLQSQNDQRGEIIH [SEQ ID 172] P14323 Peptide: TVFDGVLRPGQL [SEQ ID 199] P14323 Peptide: FGKTVFDGVLRPGQL [SEQ ID 211] P14323 Peptide: RLQSQNDQRGEIIHVK [SEQ ID 206] P14323 Peptide: QKEFLLAGNNNR (also in P14614) [SEQ ID 219]

[0248] Protein: P14614 - 3 - Rice MATIAFSRLSIYFCVLLLCHGSMAQLFGPNVNPWHNPRQGGFRECRFDRLQAFEPLRRVRSEAGVTEYFDEKNEQFQCTGTFVIRRVIEPQGLLVPRYSNTPGMVYIIQGRGSMGLTFPGCPATY QQQFQQFLPEGQSQSQKFRDEHQKIHQFRQGDIVALPAGVAHWFYNEGDAPVVALYVFDLNNNANQLEPRQKEFLLAGNNNREQQMYGRSIEQHSGQNIFSGFNNELLSEALGVNALVAKRLQGQ NDQRGEIIRVKNGLKLLRPAFAQQQEQAQQQEQAQAQYQVQYSEEQQPSTRCNGLDENFCTIKARLNIENPSHADTYNPRAGRITRLNSQKFPILNLVQLSATRVNLYQNAILSPFWNVNAHSLV YIVQGHARVQVVSNLGKTVFNGVLRPGQLLIIPQHYVVLKKAEHEGCQYISFKTNANSMVSHLAGKNSIFRAMPVDVIANAYRISREQARSLKNNRGEELGAFTPRYQQQTYPGFSNESENEALE [SEQ ID 5]

[0249] Peptide: LSEALGVNAL [SEQ ID 60] Peptide: LRPAFAQQQEQAQQQEQA [SEQ ID 61] Peptide: LRPAFAQQQE [SEQ ID 62] Peptide: LRPAFAQQQEQAQQQE [SEQ ID 63] Peptide: HNPR [SEQ ID 186] P14614 Peptide: WHN [SEQ ID 187] P14614 Peptide: TVFNGVLRPGQLL [SEQ ID 212] P14614 Peptide: LLRPAFAQQQEQAQQQEQA [SEQ ID 220] Peptide: VKNGLKLLRPAF [SEQ ID 221] Peptide: FLLAGNNNRE [SEQ ID 222] Peptide: GLKLLRPAFAQQQE [SEQ ID 223] Peptide: LKLLRPAFAQQQE [SEQ ID 224] Peptide: LLRPAFAQQQE [SEQ ID 225]

[0250] Protein: P07728 - 4 - Rice MASINRPIVFFTVCLFLLCNGSLAQQLLGQSTSQWQSSRRGSPRECRFDRLQAFEPIRSVRSQAGTTEFFDVSNEQFQCTGVSVVRRVIEEPRGLLLPHYTNGASLVYIIQGRGITGPTFPGCPE SYQQQFQQSGQAQLTESQSQSQKFKDEHQKIHRFRQGDVIALPAGVAHWCYNDGEVPVVAIYVTDLNNGANQLDPRQRDFLLAGNKRNPQAYRREVEERSQNIFSGFSTELLSEALGVSSQVARQ LQCQNDQRGEIVRVEHGLSLLQPYASLQEQEQGQVQSRERYQEGQYQQSQYGSGCSNGLDETFCTLRVRQNIDNPNRADTYNPRAGRVTNLNTQNFPILSLVQMSAVKVNLYQNALLSPFWNINA HSVVYITQGRARVQVVNNNGKTVFNGELRRGQLLIIPQHYAVVKKAQREGCAYIAFKTNPNSMVSHIAGKSSIFRALPNDVLANAYRISREEAQRLKHNRGDEFGAFTPIQYKSYQDVYNAAESS [SEQ ID 6]

[0251] Peptide: HGLSLLQPYA [SEQ ID 64] Peptide: HGLSLLQPYASL [SEQ ID 65] Peptide: HGLSLLQPY [SEQ ID 66] Peptide: RSQNIF [SEQ ID 177] P07728 Peptide: PNSM [SEQ ID 178] P07728 Peptide: MASINRPIVFFTVCLFLLCNGSLA [SEQ ID 213] Peptide: FLLAGNKRNPQ [SEQ ID 214] Peptide: FLLAGNKRN [SEQ ID 215]

[0252] Protein: P29835 - 5 - Rice MASKVVFFAAALMAAMVAISGAQLSESEMRFRDRQCQREVQDSPLDACRQVLDRQLTGRERFQPMFRRPGALGLRMQCCQQLQDVSRECRCAAIRRMVRSYEESMPMPLEQGWSSSSSEYYGGEGSSSEQGYYGEGSSEEGYYGEQQQQPGMTRVRLTRARQYAAQLPSMCRVEPQQCSIFAAGQY [SEQ ID 227]

[0253] MPMP [SEQ ID 173] P29835 PMPL [SEQ ID 174] P29835

[0254] Pea Protein 3: P15838 - 3 - MATKLLALSLFCLLLGGCFALREQPEQNECQLERNNALEPDNRIESEGGLIETNPNNKQFRCAGVALSRATLQHNALRRPYYSNAPQEIFIQQGNGYFGMVFPGCPETFEEPQESEQGEGRRYRDRHQKVNRFREGDIIAVPTGIVFWMYNDQDTPVIAVSLTDIRSSNNQLDQMPRRFYLAGNHEQEFLRYQHQQGGKQEQENEGNNIFSGFKRDFLEDAFNVNRHIVDRLQGRNEDEEKGAIVKVKGGLSIISPPEKQARHQRGSRQEEDEDEDEERQPRHQRGSRQEEEEDEDEERQPRHQRRGEEEEEDKKERRGSQKGKSRRQDNGLEETVCTAKLRLNIGPSSPDIYNPEAGRIKTVTSLDLPVLRWLKLSAEHGSLHKNAMFVPHYNLNANSIIYALKGRARLQVVNCNGNTVFDGELEAGRALTVPQNYAVAAKSLSDRFSYVAFKTNDRAGIARLAGTSSVINNNLPLDVVAATFNLQRNEARQLKSNNPFKFLVPARQSENRASA [SEQ ID 228]

[0255] LEPDNR [SEQ ID 175] P15838 GIARLAGTSSWIGN [SEQ ID 176] P15838

[0256] protein : Q0D7S0 - 3 - イネ MASNKVVFSVLLLAVVSVLAATATMAEYHHQDQVVYTPGPLCQPGMGYPPMYPLPRCRALVKRQCVGRGTAAAAEQVRRDCCRQLAAVDDSWCRCEAISHMLGGIYRELGAPDVGHPMSEVFRGCRRGDLERAAASLPAFCNVDIPNGGGGVCYWLARSGY [SEQ ID 229]

[0257] GHPM [SEQ ID 179] Q0D7S0 HPMS [SEQ ID 180] Q0D7S0

[0258] Rice Protein 8: Q6K7K6 MASMSTILPLCLGLLLFFQVSMAQFSFGGSPLQSPRGFRGDQDSRHQCRFEHLTALEATH QQRSEAGFTEYYNIEARNEFRCAGVSVRRLVVESKGLVLPMYANAHKLVYIVQGRGVFGM ALPGCPETFQSVRSPFEQEVATAGEAQSSIQKMRDEHQQLHQFHQGDVIAVPAGVAHWLY NNGDSPVVAFTVIDTSNNANQLDPKRREFFLAGKPRSSWQQQSYSYQTEQLSRNQNIFAG FSPDLLSEALSVSKQTVLRLQGLSDPRGAIIRVENGLQALQPSLQVEPVKEEQTQAYLPT KQLQPTWLRSGGACGQQNVLDEIMCAFKLRKNIDNPQSSDIFNPHGGRITRANSQNFPIL NIIQMSATRIVLQNNALLTPHWTVNAHTVMYVTAGQGHIQVVDHRGRSVFDGELHQQQIL LIPQNFAVVVKARREGFAWVSFKTNHNAVDSQIAGKASILRALPVDVVANAYRLSREDSR HVKFNRGDEMAVFAPRRGPQQYAEWQINEK [SEQ ID 230] <0OO1109>[[ID=2~3]] EWQINEK [SEQ ID 182] Q6K7K6 GPQQYAEWQINEK [SEQ ID 183] Q6K7K6 PQQYAEWQ [SEQ ID 184] Q6K7K6 ] RGPQQYA [SEQ ID ISS] Q6K7K6 RGPQQYAEWQINEK [SEQ ID 205] Q6K7K6 RGPQQYAEWQINEK [SEQ ID 208] Q6K7K6 RGPQQYAEWQIN [SEQ ID 198] Q6K7K6

[0260] Rice Protein 7: Q6K508 MATTTSLLSSCLCALLLAPLFSQGVDAWESRQGASRQCRFDRLQAFEPLRKVRSEAGDTE YFDERNEQFRCAGVFVIRRVIEPQGLVVPRYSNTPALAYIIQGKGYVGLTFPGCPATHQQ QFQLFEQRQSDQAHKFRDEHQKIHEFRQGDVVALPASVAHWFYNGGDTPAVVVYVYDIKS FANQLEPRQKEFLLAGNNQRGQQIFEHSIFQHSGQNIFSGFNTEVLSEALGINTEASKRL QSQNDQRGDIIRVKHGLQLLKPTLTQRQEEHRQYQQVQYREGQYNGLDENFCTIKARVNI ENPSRADYYNPRAGRITLLNNQKFPILNLIGMGAARVNLYQNALLSPFWNINAHSVVYII QGSVRVQVANNQGRSVFNGVLHQGQLLIIPQNHAVIKKAEHNGCQYVAIKTISDPTVSWV AGKNSILRALPVDVIANAYRISRDEARRLKNNRADEIGPFTPRFPQKSQRGYQFLTEGLS

[0261] LIGM [SEQ ID 231] GYVGLTFPGCPATHQQQFQLFEQR [SEQ ID] Q6K508

[0262] Protein: P02855 - 4 - Pea DNAEIEKILLEEHEKETHHRRGLRDKRQQSQEKNVIVKVSKKQIEELSKNAKSSSKKSVSSRESEPFNLKSSDPIYSNQYGKFFEITPKKNPQLQDLDIFVNYVEIKEGSLWLPHYNSRAIVIVTVNEGKGDFELVGQ RNENQQGLREEDDEEEEQREEETKNQVQSYKAKLTPGDVFVIPAGHPVAVRASSLNLGFGINAENNQRNFLAGEEDNVISQIQKQVKDLTFPGSAQEVDRLLENQKQSYFANAQPQQRETRSQEIKEHLYSILGAF [SEQ ID NO:232]

[0263] KNPQLQDLDIFVNYVEIK [SEQ ID 201] P02855

[0264] protein : P02857 - 1 - エンドウマメ MAKLLALSLSFCFLLLGGCFALREQPQQQNECQLERLDALEPDNRIESEGGLIETNPNNKQFRCAGVALSRATLQRNALRRPYYSNAPQEIFIQQGNGYFGMVFPGCPETFEEPQESEQGEGRRYRDRHQKVNRFREGDIIAVPTGIVFWMYNDQDTPVIAVSLTDIRSSNNQLDQMPRRFYLAGNHEQEFLQYQHQQGGKQEQENEGNNIFSGFKRDYLEDAFNVNRHIVDRLQGRNEDEEKGAIVKVKGGLSIISPPEKQARHQRGSRQEEDEDEEKQPRHQRGSRQEEEEDEDEEERQPRHQRRRGEEEEEDKKERGGSQKGKSRRQDNGLEETVCTAKLRLNIGPSSPDIYNPEAGRIKTVTSLDLPVLRWLKLSAEHGSLHKNAMFVPHYNLNANSIIYALKGRARLQVVNCNGNTVFDGELEAGRALTVPQNYAVAAKSLSDRFSYVAFKTNDRADIARLAGTSSVINNNLPLDVVAATFNLQRNEARQLKSNNPFKFLVPARESENRASA [SEQ ID 233]

[0265] LDALEPDNR [SEQ ID 202] P02857

[0266] protein : P09918 - 14 - Pisum sativum MFSGVTGILNRGHKIKGTVVLMRKNVLDINSLTTVGGVIGQGFDILGSTVDNLTAFLGRSVSLQLISATKPDATGKGKLGKATFLEGIISSLPTLGAGQSAFKIHFEWDDMGIPAGAFYIKNFMQTEFFLVSLTLDDIPNHGSIYFVCNSWIYNAKHHKIDRIFFANQTYLPSETPAPLVHYREEELNNLRGDGTGERKEWERIYDYDVYNDLGNPDSGENHARPVLGGSETYPYPRRGRTGRKPTRKDPNSESRSDYVYLPRDEAFGHLKSDFLTYGLKAVSQNVVPALESVFFDLNFTPNEFDSFDEVHGLYEGGIKLPTNILSQISPLPVLKEIFRTTDGENTLKYPPPKVIQVSRSGWMTDEEFAREMLAGVNPNVICCLQEFPPRSKLDSQIYGDHTSKISKEHLEPNLEGLTVEEAIQNKKLFL LDHHDSIMPYLRRINSTSTKAYATRTILFLNNNQNLKPLAIELSLPHPQGDEHGAVSYVYQPALEGVESSIWLAKAYVIVNDSCYHQLVSHWNLTHAVVEPFVIATNRHLSCLHPIYKLLYPHYRDTMNINSLARLSLVNDGGIIEKTFLWGRYSMEMSSKVYKNWVFTEQALPADLIKRGMAIEDSPSPCGVKLVVEDYPYAVDGLEIWAIIK TWVQDYVSLYYTSDEKLRQDSELQAWWKELVEVGHGDKKNEPWWPKMQTREDLIEVCSIVIWTASALHAAVNFGQYSYGGLILNRPTLSRRFMPEKGSAEFEELVKSPQKAYLKTITPKFQTLIDLSVIEILSRHASDELYLGERDNPNWTSDKRALEAFKKFGNKLAEIEKKLTQRNNDEKLRNHGPVEMPYTLLYPSSKEGLTFRGIPNSISI [SEQ ID NO:234]

[0267] HGPVEMPYTLLYPSSK [SEQ ID 209] P09918

[0268] LGLSPQDALK [SEQ ID 210] Q43819

[0269] WDP [SEQ ID 188] B5A8N6 PVEMPTLLYPS [SEQ ID 197]

[0270] Remove the snowflake from the snowflake

[0271] P13918 (Carlington) >gi|137584|sp|P08438.1|VCL_VICFA RecName: Full=Vicillin; Flags: Precursor [Vice faba] >gi|22057|emb|CAA68559.1| vicilin [Vicia faba var. minor] >gi|383931031|gb|AFH56916.1| vicilin [Vica faba] MAATTLKDSFPLLTLLGIAFLASVCLSSRSRDQDNPPFVFESNRFQTLFENENGHIRLLQKFDQHSKLLENLQNYRLLEYKSKPHTIFLPQTDADFILVLSGKAILTVLLPNDRN SFSLERGDTIKLPAGTIGYLVNRDDEEDLRVLDLVIPVNRPGEPQSFLLSGNQNQPSILSGSKNILEASFNTDYKEIEKVLLEEHGKEKYHRRGLKDRRQRGQEENVIVKISRKQ IEELNKNAKSSSKKSTSSEPFNLRREPIYSNKFGKFFEITPKRNPQDLQDLNIFVNYVEINEGSLLLPHYNSRAIVTVNEGKGDFELVGQRNENQQGLREEYDEEKEQGEEE IRKQVQNYKAKLSPGDVLVIPAGYPVAIKASSNLNLVGFGINAENNQRYFLAGEEDNVISQIHKPVKELAFPGSAQEVDTLENQQSHFANAQPRERERGSQEIKDHLYSILGSF [SEQ ID 67]

[0272] >gi|502105533|ref|XP_004492829.1| PREDICTED: vicilin-like isoform X1 [Cicer arietinum] ChickPea MAIKARFPLLVLLGIVFLASVCAKSDKENPFFFKSNNCQTLFENENGHVRLLQRFDKRSQLFENLQNYRLMEYNSKPHTLFLPQHNDADFILVVLRGRAILTVLNPNDRNT FKLERGDTIKLPAGTIAYLANRDDNEDLRVLDLAIPVNRPGQFQSFSLSGNENQQSYFQGFSKKILEASFNSDYEEIERVLLEEQEQKPEQRRGHKGRQQSQETDVIVKISR EQIEELSKNAKSNCKKSVSSESEPFNNLRSRSPIYSNRFGNFFEITPEKNPQLKDLDIFVNSVEIKEGSLLLPHFNSRATVILVVNEGKGEVELVGLRNENEQENKKEDEEE EEDRNVQVQRFQSKLSSGDVVVIPASHPFSINASSDLFLLGFGINAQNNQRNFLAGEEDNVISQIQRPVKEVAFPGSAEEVDRLLKNQRQSHFANAQPQQKRKGSQRIRSPF [SEQ ID 68]

[0273] >gi|29539109|emb|CAD87730.1| allergen Len c 1.0101 [Lens culinaris] Lentil SRSDQENPFIFKSNRFQTIYENENGHIRLLQRFDKRSKIFENLQNYRLLEYKSKPHTIFLPQFTDADFILVVLSGKAILTVLNSNDRNSFNLERGDTIKLPAGTIAYLANRDDNEDLRVLDLAIPVNRPGQLQSFLLSGTQNQPSFLSGFSKNILEAAFNTEYEEIEKVLLEEQEQKSQHRRSLRDKRQEITNEDVIVKVSREQIEELSKNAKSSSKKSVSSESEPFNLRSRNPIYSNKFGKFFEITPEKNPQLQDLDIFVNSVEIKEGSLLLPNYNSRAIVIVTVNEGKGDFELVGQRNENQQEQREENDEEEGQEEETTKQVQRYRARLSPGDVLVIPAGHPVAINASSDLNLIGFGINAKNNQRNFLAGEEDNVISQIQRPVKELAFPGSSREVDRLLTNQKQSHFANAQPLQIE [SEQ ID 69]

[0274] Q9M3X6 (エンドウマメ) >gi|164512526|emb|CAP06312.1| cvc [Pisum abyssinicum] MATTVESRFPLLLFPGIIFLASVCVTYANYDEGSETRVPGQRERGRQEGEKEEKRHGEWRPSYEKEEDEEEKQKYRYQREKEDEEEKQKYRYQREKKEEKEVQPGRERWEREEDEEQVDEEWRGSQRRQDPEERARLRHREERTKRDRRHKREGEEEERSSESQEQRNPFLFKSNKFLTLFENENGHIRRLQRFDKRSDLFENLQNYRLVEYRAKPHTIFLPQHIDADLILVVLNGKAILTVLSPNDRNSYNLERGDTIKIPAGTTSYLVNQDDEEDLRVVDFVIPVNRPGKFEAFGLSENKNQYLRGFSKNILEASLNTKYETIEKVLLEEQEKKPQQLRDRKRRQQGGERDAIIKVSREQIEELRKLAKSSSKKSLPSEFEPFNLRSHKPEYSNKFGKLFEITPEKKYPQLQDLDILVSCVEINKGALMLPHYNSRAIVVLLVNEGKGNLELLGLKNEQQEREDRKERNNEVQRYEARLSPGDVVIIPAGHPVAISASSNLNLLGFGTNAENNQRNFLSGSDDN [SEQ ID 70]

[0275] >gi|164512538|emb|CAP06318.1| cvc [Lathyrus annuus] MATTIKSRFPLLLLLGIIFLASVCVTWANYDEGSEPRVPGQRERGRQEGEKEEKRHGEWRPSYEEEYDEGLEPKVPGKRERGRQEGEKEEKRHEEWRPSEKEEDEEEKQKYNYQREKKEHKEVQPGRERWERKQQ DECQVEEDEEPGEEQWRGSKRHEDPERARLRHREEKTKSYVEDNEETSSKEGRNPFLFKSNKFLTLFENENGHIRRLQRFDERSDIFENLQNYRLVEYRAKPHTMFLPQHIDADLILVVLNGKAILTVLSPNDR NSYNLERGDTVKLPAGTTSYLVNQDDEEDLRVVDLAIPVNRPGKFEAFGLSANKNQYLRGFSKNILEASLNTKYETIEKVLLEERRDQKGRQQGQETNAIVKVSREQIEELRKLAKSSSKSSLLSEPLNLRSQ NPKYSNKFGKFFEITPQKKYPQLQDLDVSISCVEINKGALLLPHYNSRSIGILVNEGKGNLELVGFKNEQRQRENEETNKKLQRYEARLSSGDVVVIPEGHPVAISASSNLNLLGFGINAANNQRNFLTGSDDN [SEQ ID 71]

[0276] >gi|164512558|emb|CAP06328.1| cvc [Villa villosa] MATTIKSRFPVLLLLGIIFLTSVCVTYANYDEGREPSVPGQRERGRQEGEKEEKRHGEWRPSEEDEEEKYKYEEGRVPGQRERGRQEGEKEEKRHGKWRPSEEEEDEEEKYRYEEGSEPRGPGQRETGRQEGEKEKQRPEREPSYEKE EDEEEKQKYQYHREKKEQREVRPGRERFHEDEEQWRGIQRHEDPEERARERYRAEIAKRQVEEEREERDIPHEREQRNPFLFKSNKFQTLFQNENGYIRRLQRFDKRSDLFENLQNYRLVEYRAKPHTIFLPQHIDADLIIVVLS GRAILTVLSPDDRNSYNLERGDTIKLPAGTSYLVNQDDEEDLRVVDLAIPVNRPGKVESFLLSGNKNQYLRGFSKNILEASFNTNYETIERVLLEEQDKESQSIGQRRSQRQETNALVKVSREQLEDLKRLAKSSSQELSSQF EPINLRSQNPKYSNKFGKVFEITPEKKYPQLQDLFVSSVDIKEGALMLPHYNSRAIVVLLVNEGRGNLELVGLKNEQQREKEDEQERNNQVQRYEARLSPGDVVIIPAGHPVAVRASSDLNLLAFGINAENNQRNFLAGSDNFLAGSDN [SEQ ID 72]

[0277] Q0DEV5 (イネ) >gi|83375868|gb|ABC17777.1| waxy [Oryza rufipogon] MSALTTSQLATSATGFGIADRSAPSSLLRHGFQGLKPRSPAGGDATSLSVTTSARATPKQQRSVQRGSRRFPSVVVYATGAGMNVVFVGAEMAPWSKTGGLGDVLGGLPPAMAANGHRVMVISPRYDQYKDAWDTSVVAEIKVADRYERVRFFHCYKRGVDRVFVDHPSFLEKVWGKTGEKIYGPDTGVDYKDNQMRFSLLCQAPRILNLNNNPYFKGTYGEDVVFVCNDWHTGPLASYLKNNYQPNGIYRNAKVAFCIHNISYQGRFAFEDYPELNLSERFRSSFDFIDGYDTPVEGRKINWMKAGILEADRVLTVSPYYAEELISGIARGCELDNIMRLTGITGIVNGMDVSEWDPSKDKYITAKYDATTAIEAKALNKEALQAEAGLPVDRKIPLIAFIGRLEEQKGPDVMAAAIPELMQEDVQIVLLGTGKKKFEKLLKSMEEKYPGKVRAVVKFNAPLAHLIMAGADVLAVPSRFEPCGLIQLQGMRYGTPCACASTGGLVDTVIEGKTGFHMGRLSVDCKVVEPSDVKKVAATLKRAIKVVGTPAYEEMVRNCMNQDLSWKGPAKNWENVLLGLGVAGSAPGIEGDEIAPLAKENVAAP [SEQ ID 73]

[0278] >gi|297614332|gb|ADI48504.1| glycogen synthetase [Oryza officinalis] MSALTTSQLATSATGFGIADRSAPSSLLRHGFQGLKPRSPAGGDASSLSVTTSARATPKQQRSVQRGSRRFPSVVVYATGAGMNVVFVGAEMAPWSKTGGLGDVLGGLPPAMAANGHRVMVISPRHDQYKDAWDTSVVAEIKVADRYERVRFFHCYKRGVDRVFIDHPSFLEKVWGKTGEKIYGPDTGVDYKDNQMRFSLLCQAALEAPRILNLNNNPYFKGTYGEDVVFVCNDWHTGPLPSYLKNNYQPNGIYRNAKVAFCIHNISYQGRFAFEDYPELNLSERFRSSFDFIDGYDTPVEGRKINWMKAGILESDRVLTVSPYYAEELISGIARGCELDNIMRLTGITGIVNGMDVSEWDPSKDKYIAAKYDATTAIEAKALNKEALQAEAGLPVDRKIPLIAFIGRLEEQKGPDVMAAAIPELMQENVQIVLLGTGKKKFEKLLKSMEEKYPGKVRAVVKFNAPLAHLIMAGADVLAVPSRFEPCGLIQLQGMRYGTPCACASTGGLVDTVIEGKTGFHMGRLSVDCKVVEPSDVQKVATTLKRAIKIVGTPAYNEMVRNCMNQDLSWKGPAKNWENVLLGLGVAGSAPGVEGEEIAPLAKENVAAP [SEQ ID 74]

[0279] >gi|389620054|gb|AFK93486.1| granule-bound starch synthase [Hordeum vulgare subsp. vulgare] MAALATSQLATSGTVLGVTDRFRRPGFQGLRPRNPADAALGMRTIGASAAPKQSRKAHRGSRRCLSVVVRATGSGMNLVFVGAEMAPWSKTGGLGDVLGGLPAMAANGHRVMVVSPRYDQYKDAWDTSVISEIKVADEYERVRFFHCYK RGVDRVFIDHPWFLEKVRGKTKEKIYGPDAGTDYEDNQQRFSLLCQAALEAPRILNLNNNPYFSGPYGEDVVFVCNDWHTGLLLACYLKSNYQSNGIYRTAKVAFCIHNISYQGRFSFDFAQLNLPDRFKSSFDFIDGYDKPVEGRKINWM KAGILQADKVLTVSPYYAEELISDEARGCELDNIMRLTGITGIVNGMDVSEWDPTKDKFLAVNYDITTALEAKALNKEALQAEVGLPVDRKVPLVAFIGRLEEQKGPDVMIAAIPEILKEEDVQIILLGTGKKKFEKLLKSMEEKFPGKVRAVVRFNAPLAHQMMAGADLLAVTSRFEPCGLIQLQGMRYGTPCVCASTGGLVDTIVEGKTGFHMGRLSVDCNVVEPADVKKVATTLKRAVKVVGTPAYQEMVKNCMIQDLSWKGPAKNWEDVLLELGVEGSEPGIVGEEIAPLAMENVAAP [SEQ ID 75]

[0280] P14323 (イネ) >gi|573918992|ref|XP_006647120.1| PREDICTED: glutelin type-B 2-like [Oryza brachyantha] MATTVFSRFSTYFCVLLLCHGSMAQLFNPSTNPWHNPRQGSSRECRFDRLQPFEPLRKVRSEAGVTEYFDEKNELFQCTGTFVIRRVIQPQGLLVPRYTNAPGLVYIIQGRGSIGLTFPGCPATYQQQFQQFLPQEQSQSQKFRDEHQKIHQFRQGDIVALPAGVAHWFYNDGDAPVVAVYVYDVKNSANQLEPRQREFLLGGNNMRAQQVYGSSAEQHSRQNIFSGFGVEILSEALGISTVTTKRLQSQNDQRGEIIHVKNGLQFLKPTLTQQQEQAQAQYQEVQYSEQQQTSSRWNGLDENFCTIKARMNIENTSRADTYNPRAGRTTSLNSQKFPILNLVQMSATRVNLYQNAILSTFWNVNAHSLVYTIQGRARVQVVSNFGKTVFDGELRPGQLLIIPQHYVVLKKAQREGFRYIAIKTNANAFVSQLVGKNSVFRSLPVDVIANVYRISREQARSLKNNRGEEHGAFAPRSQQQSYPGFSNQSESETSE [SEQ ID 76]

[0281] >gi|573919041|ref|XP_006647142.1| PREDICTED: glutelin type-B 4-like [Oryza brachyantha] MATTTFSRFSIYFCVLLLCHGSMAQLFSPTLNPWHSSRRGGSRDCRFDRLQAFEPLRRVRSEAGVTEYFDERNEQFQCTGTFVIRRVIEPQGLLVPRYTNTPGVVYIMQGRGSMGLTFPGCPATYQQQFQQFLPEGQSQSQKFRDEHQKIHQFRQGDIVALPAGVAHWFYNEGDTPVVALYVFDINNSANQLEPRQKDFLLAGNNNREQQVYGRSIEKHSGQNIFSGFNHELLSEALGISTLAAKRLQGQNDHRGEIIRVRNGLQLLKPTFTQQQEQAQSQYQVQYSEKQQESTRCNGLDENFCTINARLNIENPSRADTYNPRAGRITHLNNQKFPILNLVQMSATRVNLYQNAILSPYWNVNAHSLVYMVQGHARVQVVSNLGKTVFNSVLRPGQLLIIPQHYVVLKKAEREGCQYIAFKTNANSIVSQLAGKNSILRAMPVDVVANAYRISREQARDLKNNRGEELGAFTPKFEQQSYPGLSNESESEASE [SEQ ID 77]

[0282] >gi|109894635|gb|ABG47337.1| glutelin precursor [Zizania latifolia] MNMATINGPTIFFTVCLFLLCGHSLAQLLGQSTSQWQSSHRGSSRQCRFDRLQAFEPVRSVRSQAGTTEFFDASNELFQCAGVSIVRRIIEPRGLLLPQYTNGATIMYIIQGRGITGQTFPGCPESYQQQFQQSMQAQLTGSQSQKFKDEHQKINRFRQGDVIALPAGVAHWCYNDGEVPVVAIYVIDINNAAANQLDPRQRDFLLAGNMRSPQAYRREVENQSQNIFSGFSAELLSEALGISTGVARQ LQCQNDQRGEIVRVEHGLSLLQPYASLQEQEQKQEQPRERYQVTQHQQSQYGGGCSNGLDETFCAMRIWQNIDNPNLADTYNPRAGRVTNLNSQKFPILNLIQMSAVKVNLYQNALSPFWNISHSVVYVTQGCARVQVVNNNGKTVFNGELRRGQLLIIPQHYVVVKKAQREGCAYIAFKTNPNSMVSHIVGKSSIFRALPTDVLANAYRISREDAQRLKHNRGDELGAFTPLQYKQDVSSVAASS [SEQ ID 78]

[0283] P14614 (イネ) >gi|115445309|ref|NP_001046434.1| Os02g0248800 [Oryza sativa Japonica Group] >gi|37993738|gb|AAR06952.1| glutelin type-B [Oryza sativa Japonica Group] >gi|47497729|dbj|BAD19794.1| glutelin type-B [Oryza sativa Japonica Group] >gi|113535965|dbj|BAF08348.1| Os02g0248800 [Oryza sativa Japonica Group] >gi|215768942|dbj|BAH01171.1| unnamed protein product [Oryza sativa Japonica Group] >gi|284431772|gb|ADB84627.1| glutelin [Oryza sativa Japonica Group] MTISVFSRFSIYFCVLLLCNGSMAQLFDPATNQWQTHRQGSFRECRFERLQAFEPLQNVRSEAGVTEYFDETNELFQCTGTFVIRRVIQPQGLLIPRYANTPGMVYIIQGRGSMGLTFPGCPATYQQQSQQFLFQGESQSQKFIDEHQKIHQFRQGDIVVLPTGVAHWFYNDGDTPVVALYVYDINNSANQLEPRHREFLLAGKNNRVQQVYGRSIQQHSGQNIFNGFSVEPLSEALNINTVTTKRLQSQNDQRGEIIHVKNGLQLLKPTLTQRQEQEQAQYQEVQYSEKPQTSSRWNGLEENLCTIKTRLNIENPSRADSYDPRAGRITSLDSQKFPILNIIQMSATRVNLYQNAILTPFWNVNAHSLMYVIRGRARVQVVSNFGKTVFDGVLRPEQLLIIPQNYVVLKKAQHEGCQYIAINTNANAFVSHLAGVDSVFHALPVDVIANAYCISREEARRLKNNRGDEYGPFPPRLQQQIYPEFSNESKGETSE [SEQ ID 79]

[0284] >gi|428674402|gb|AFZ41188.1| glutelin, partial [Oryza sativa Japonica Group] LLCHGSMAQIFSLGINPWQNPRQGGSRECRFDRLQAFEPLRKVRHEAGVTEYFDEKNEQFQCTGTLVIRRIIEPQGLLLPRYSNTPGLVYIIQGTGVLGLTFPGCPATYQKQFRHFGLEGGSQRQGKKLRDENQKIHQFRQGDVVALPSGIPHWFYNEGDTPVVALFVFDVNNNANQLEPRQKEFLLAGNNIEQQVSNPSINKHSGQNIFNGFNTKLLSEALGVNIEVTRRLQSQNDRRGDIIRVKNGLRLIKPTITQQQEQTQDQYQQIQYHREQRSTSKYNGLDENFCAIRARLNIENPNHADTYNPRAGRITNLNSQKFSILNLVQMSATRVNLYQNAILSPFWNINAHSLVYTIQGRARVQVVSNHGKAVFNGVLRPGQLLIIPQNYVVMKKAELEGFQFIAFKTNPNAMVNHIAGKNSVLRAMPVDVIANAYRISRQEARSLKNNRGEEIGAFTPRYQQQKIHQEYSNPNESETQ [SEQ ID 80]

[0285] >gi|226510|prf||1515394A seed storage globulin MATTRFPSLLFYSCIFLLCNGSMAQLFGQSFTPWQSSRQGGLRGCRFDRLQAFEPLRQVRSQAGITEYFDEQNEQFRCAGVSVIRRVIEPQGLLLPQYHNAPGLVYILQGRGFTGLTFPGCPATFQQQF QPFDQARFAQGQSKSQNLKDEHQRVHHIKQGDVVALPAGIVHWCYNDGDAPIVAVYVFDVNNNQLEPRQKEFLAGNNKREQFGQNIFSGFSVQLLSEALGISQQAAQQQNDQRGEIIRVSQGL QFLKPFVSQQGPVEHQAYQPIQSQQEQSTQYQVGQSPQYQEGQSTQYQSGQSWDQSFNGLEENFCSLEARQNIENPKRADTYNPRAGRITHLNSKNFPTLNLVQMSATRVNLYQNAILSPYWNINAHSV MHMIQGRARVQVVNNHGQTVFNDILRRGQLLIIPQHYVVLKKAEREGCQYISFKTTPNSMVSYIAGKTSILRALPVDVLANAYRISRQESQNLKNNRGEEFGAFTPKFAQTGSQSYQDEGESSSTEKASE [SEQ ID 81]

[0286] P07728 (イネ) >gi|531874314|gb|AGT59174.1| glutelin, partial [Oryza sativa Indica Group] CRFDRLQAFEPIRSVRSQAGTTEFFDVSNEQFQCTGVSAVRVIEPRGLLLPHYTNGASLVYIIQGRGITGPTFPGCPESYQQFQQSGQQLTESQSQSHKFKDEHQKIHRF RQGDVIALPAGVAHWCYNDGEVPVVAIYVTDLNNGANQLDPRQRDFLAGNKRNPQAYRREVEERSQNIFSGFSTELLSEALGVSSQVARQLQCQNDQRGEIVRVEHGLSLLQP YASLQEQGQVQSRERYQEGQYQQSQYGSGCSNGLDETFCTMKVRQNIDNPNRADTYNPRAGRVTNLNTQNFPILNLVQMSAVKVNLYQNALLSPWNINAHSSVVYITQGRA RVQVVNNNGKTVFNGELRRGQLLIIPQHYAVVKKAQREGCAYIAFKTNPNSMVSHIAGKSSIFRALPNDVLANAYRISREEAQRLKHNRGDEFGAFTPIQYKSYQDVYNAAESS [SEQ ID 82]

[0287] >gi|109894635|gb|ABG47337.1| glutelin precursor [Zizania latifolia] MNMATINGPTIFFTVCLFLLCHGSLAQLLGQSTSQWQSSHRGSSRQCRFDRLQAFEPVRSVRSQAGTTEFFDASNELFQCAGVSIVRRIIEPRGLLLPQYTNGATIMYIIQGRGITGQTFPGCPESYQQQFQQSMQAQLTGSQSQSQKFKDEHQKINRFRQGDVIALPAGVAHWCYNDGEVPVVAIYVIDINNAANQLDPRQRDFLLAGNMRSPQAYRREVENQSQNIFSGFSAELLSEALGISTGVARQLQCQNDQRGEIVRVEHGLSLLQPYASLQEQEQKQEQPRERYQVTQHQQSQYGGGCSNGLDETFCAMRIWQNIDNPNLADTYNPRAGRVTNLNSQKFPILNLIQMSAVKVNLYQNALLSPFWNINSHSVVYVTQGCARVQVVNNNGKTVFNGELRRGQLLIIPQHYVVVKKAQREGCAYIAFKTNPNSMVSHIVGKSSIFRALPTDVLANAYRISREDAQRLKHNRGDELGAFTPLQYKSYQDVSSVAASS [SEQ ID 83]

[0288] >gi|472867|emb|CAA52764.1| 11S globulin [Avena sativa] MATTSFPSMLFYFCIFLLFHGSMAQLFGQSSTPWQSSRQGGLRGCRFDRLQAFEPLRQVRSQAGITEYFDEQNEQFRCTGVSVIRRVIEPQGLVLPQYHNAPALVYILQGRGFTGLTFPGCPATFQQQFQPFDQSQFAQGQRQSQTIKDEHQRVQRFKQGDVVALPAGIVHWCYNDGDAPIVAIYVFDVNNNANQLEPRQKEFLLAGNNKREQQSGNNIFSGLSVQLLSEALGISQQAAQRIQSQNDQRGEIIRVSQGLQFLKPIVSQQVPGEQQVYQPIQTQEGQATQYQVGQSTQYQVGKSTPYQGGQSSQYQAGQSWDQSFNGLEENFCSLEARKNIENPQHADTYNPRAGRITRLNSKNFPILNIVQMSATRVNLYQNAILSPFWNINAHSVIYMIQGHARVQVVNNNGQTVFNDILRRGQLLIVPQHFVVLKKAEREGCQYISFKTNPNSMVSHIAGKSSILRALPIDVLANAYRISRQEARNLKNNRGEEFGAFTPKLTQKGFQSYQDIEEGSSSPVRASE [SEQ ID 84]

Claims

1. A glucose transport enhancing peptide consisting of the sequence of SEQ ID NO: 154, or a glucose transport enhancing variant of said sequence having 1 to 3 amino acid changes compared to said sequence, wherein the or each amino acid change is selected from an amino acid insertion, addition, deletion and substitution.

2. 2. The glucose transport enhancing peptide of claim 1, wherein the variant has 1 to 3 amino acid changes at terminal positions.

3. 3. The glucose transport enhancing peptide of claim 2, wherein the mutant has a deletion of one amino acid at a terminal position.

4. 3. The glucose transport enhancing peptide of claim 2, wherein the variant has an addition of three amino acids at the terminal positions.

5. The glucose transport enhancing peptide of any one of claims 1 to 4, wherein the variant comprises the sequence LAIPVNR.

6. 2. The glucose transport-enhancing peptide of claim 1, wherein the variant has the sequence of SEQ ID NO: 7, 152, or 153.

7. 7. Modified peptides, including the glucose transport enhancing peptides of any one of claims 1 to 6, optionally chemically modified by side chain modifications, incorporation of protecting groups, incorporation of unnatural amino acids and / or their derivatives during peptide synthesis, and the use of cross-linking agents and other methods that impose conformational constraints on the peptide.

8. 10. A conjugate comprising the glucose transport enhancing peptide of any one of claims 1 to 6, or the modified peptide of claim 7, conjugated to a binding partner configured to increase the half-life or lipophilicity of the conjugate compared to the half-life or lipophilicity of the peptide.

9. A composition comprising the glucose transport-enhancing peptide of any one of claims 1 to 6, the modified peptide of claim 7, or the conjugate of claim 8.

10. 10. The composition of claim 9, which is a powder.

11. 11. A food, beverage, dietary supplement or food for specific medical purposes comprising the composition of claim 9 or 10.

12. A non-therapeutic method for improving muscle condition in a human or an animal, comprising administering to said human or an animal a peptide according to any one of claims 1 to 6, a modified peptide according to claim 7, a conjugate according to claim 8, a composition according to claim 9 or 10, or a food, beverage, dietary supplement or food for specific medical purposes according to claim 11.

13. 12. A glucose transport enhancing peptide according to any one of claims 1 to 6, a modified peptide according to claim 7, a conjugate according to claim 8, a composition according to claim 9 or 10, or a food, beverage, dietary supplement or food for specific medical purposes according to claim 11, for use in the treatment of a disease or condition characterized by lethargy or low energy levels in a human or animal.

14. 12. A glucose transport-enhancing peptide according to any one of claims 1 to 6, a modified peptide according to claim 7, a conjugate according to claim 8, a composition according to claim 9 or 10, or a food, beverage, dietary supplement or food for specific medical purposes according to claim 11, for use in the treatment or prevention of a metabolic disorder in a mammal characterized by dysregulated glucose or insulin levels.

15. 12. The glucose transport-enhancing peptide of any one of claims 1 to 6, the modified peptide of claim 7, the conjugate of claim 8, the composition of claim 9 or 10, or the food, beverage, dietary supplement, or food for specific medical purposes of claim 11, for use in improving glycemic control in a mammal by one or more of lowering plasma blood glucose levels, treating or preventing hyperglycemia, increasing postprandial insulin secretion, regulating glucose homeostasis, and reducing or attenuating insulin resistance.

16. 12. A glucose transport enhancing peptide according to any one of claims 1 to 6, a modified peptide according to claim 7, a conjugate according to claim 8, a composition according to claim 9 or 10, or a food, beverage, dietary supplement or food for specific medical purposes according to claim 11, for use in the treatment of sarcopenia in elderly humans.

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