WO2013129220A1 - Produit pharmaceutique ou aliment contenant un peptide - Google Patents

Produit pharmaceutique ou aliment contenant un peptide Download PDF

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Publication number
WO2013129220A1
WO2013129220A1 PCT/JP2013/054289 JP2013054289W WO2013129220A1 WO 2013129220 A1 WO2013129220 A1 WO 2013129220A1 JP 2013054289 W JP2013054289 W JP 2013054289W WO 2013129220 A1 WO2013129220 A1 WO 2013129220A1
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Prior art keywords
dipeptide
pharmaceutical
analog
peptide
anxiety
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PCT/JP2013/054289
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English (en)
Japanese (ja)
Inventor
耕作 大日向
絢子 山田
貴文 水重
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国立大学法人京都大学
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Publication of WO2013129220A1 publication Critical patent/WO2013129220A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06147—Dipeptides with the first amino acid being heterocyclic and His-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to pharmaceuticals or pharmaceutical compositions such as lifestyle-related disease therapeutic agents, diabetes therapeutic agents, anti-anxiety agents, sleep-improving agents, schizophrenia therapeutic agents, and antidepressants.
  • the present invention also relates to a food for improvement of lifestyle-related diseases including diabetes, anti-anxiety or sleep improvement.
  • the present invention further relates to methods for preventing or treating lifestyle-related diseases, diabetes, anxiety, sleep disorders, schizophrenia or depression, and uses for preventing or treating these diseases.
  • Patent Document 1 describes that ⁇ -lactotensin (His-Ile-Arg-Leu), a physiologically active peptide derived from whey protein, has a cholesterol-lowering effect upon oral administration, and a fragment of ileal contractile peptide derived from ⁇ -casein. Leu-Ser-Arg is disclosed to have an effect of lowering serum cholesterol.
  • the present inventor prevents or treats functional materials having no side effects and having both lifestyle-related disease improving action and anti-anxiety activity, pharmaceuticals and foods containing the same, diseases such as lifestyle-related diseases, and diseases
  • the purpose is to provide for use.
  • the inventors of the present invention have focused on reducing mental stress and improving lifestyle-related diseases, and have isolated a new peptide having both an anxiolytic effect and an insulin sensitivity enhancing effect.
  • the present invention provides the following pharmaceuticals or pharmaceutical compositions, foods for improving lifestyle-related diseases, improving sugar / lipid metabolism, anti-anxiety or sleep-improving foods.
  • Item 1 A pharmaceutical or pharmaceutical composition comprising as an active ingredient a dipeptide containing Met (M) or an analog thereof and His (H) or an analog thereof.
  • Item 2. The pharmaceutical or pharmaceutical composition according to Item 1, wherein the analog of Met (M) is Cys (C).
  • the pharmaceutical or pharmaceutical composition according to Item 1, wherein the analog of His (H) is Tyr (Y), Phe (F) or Trp (W).
  • Composition Item 7.
  • a food for improving lifestyle-related diseases, anti-anxiety or sleep comprising adding Met (M) or an analog thereof and a dipeptide containing His (H) or an analog thereof.
  • Item 8. The food according to Item 7, wherein a dipeptide selected from the group consisting of MH, MY, MF, MW, HM, YM, FM and WM is added.
  • Item 9. The food according to Item 7 or 8, wherein a dipeptide represented by MH is added.
  • Item 11. The method according to Item 10, wherein the dipeptide is selected from the group consisting of MH, MY, MF, MW, HM, YM, FM and WM.
  • dipeptide comprising Met (M) or an analog thereof and His (H) or an analog thereof for preventing or treating lifestyle-related diseases, diabetes, anxiety, sleep disorders, schizophrenia or depression.
  • Item 14. The use according to Item 13, wherein the dipeptide is selected from the group consisting of MH, MY, MF, MW, HM, YM, FM and WM.
  • Item 15. Item 15. The use according to Item 13 or 14, wherein the dipeptide is MH.
  • the drug or food of the present invention is effective by oral administration.
  • natural short-chain peptides can be ingested as food and do not lead to diseases, but individuals with lifestyle-related diseases including diabetes, anxiety and sleep problems may be ingested as food. Can be expected to prevent.
  • the peptide of the present invention is an enzyme digest of cochlear ⁇ -lactoglobulin, side effects are not a problem. Moreover, since milk ⁇ -lactoglobulin is contained in a large amount in milk, it can be produced at low cost.
  • the peptide which is an active ingredient of the present invention can be obtained by digesting whey protein produced in large quantities in the cheese production process with an enzyme for food additives. Since this peptide enhances insulin sensitivity, it can be expected to improve energy metabolism. This is the first dipeptide that has both an anxiolytic effect and an energy metabolism improving effect.
  • the peptide of the present invention can be taken daily by humans, domestic animals (cattle, pigs, sheep, etc.), pets (dogs, cats), etc., and lifestyle-related diseases including diabetes, anxiety, sleep disorders, insulin resistance, etc. It is effective in improving
  • the anxiolytic action can be evaluated by an elevated plus-maze test developed and widely used as an anxiety-related behavior evaluation method for screening anxiolytic drugs (Fig. 1). Specifically, an anxiolytic candidate substance is administered orally or intraperitoneally, and after 30 minutes, the mouse is placed in the elevated plus maze, and the change in the number of intrusions into the open arm and the staying time on the open arm is indicated. As described above, the strength of the anti-anxiety action can be evaluated.
  • the medicament or pharmaceutical composition of the present invention has an anxiolytic action, it may be useful as a preventive or therapeutic agent for depression, an anxiolytic agent, a sleep improving agent, and the like.
  • insulin tolerance test in the present invention, improvement in insulin resistance can be evaluated by an insulin tolerance test (ITT).
  • ITT insulin tolerance test
  • a candidate substance for an insulin sensitizer is given to mammals (human, dog, cow, pig, goat, horse, 3 hours before insulin administration). Rats, mice, rabbits, hamsters) orally, intravenously or intraperitoneally, blood glucose level is measured 0 to 1 hour after insulin administration, and insulin resistance The strength of the improvement action can be evaluated.
  • the animal to be administered may be a healthy mammal, and is preferably an insulin resistant model animal.
  • model animals for insulin resistance for example, FLS mice (naturally occurring fatty liver model animals), ob / ob mice, db / db mice, KK mice, KKAy mice, Akita mice, SDT rats, OLETF rats, TSOD mice, NSY Examples include mice, Wistar fatty rats, Zucker fatty rats, GK rats, and insulin resistant / sarcopenia model rats (high-fat high-carbohydrate diet long-term intake SD rats that show insulin resistance with age).
  • the preferred active ingredient of the present invention is effective by oral administration.
  • the present inventor has found that among protease hydrolysates of ⁇ -lactoglobulin, which is the main protein of milk / whey, MH or an analog thereof has two actions of anxiolytic and insulin sensitivity enhancement. .
  • the active ingredient of the pharmaceutical / pharmaceutical composition and food of the present invention is MH or an analog thereof.
  • the peptide has 2 to 8, preferably 2 to 7, more preferably 2 to 6, more preferably 2 to 5, particularly preferably 2 to 4 having M (Met) and H (His). Most preferred is a peptide consisting of 2 to 3 amino acids.
  • the preferred peptide of the present invention is a bovine milk-derived ⁇ -lactoglobulin, wherein MH or 2 to 8 amino acids derived from ⁇ -lactoglobulin are added to the N-terminal or C-terminal thereof, preferably
  • the peptide consists of 2 to 7, more preferably 2 to 6, further preferably 2 to 5, particularly preferably 2 to 4, and most preferably 2 to 3 amino acids.
  • a preferred peptide of the present invention is a reverse sequence HM or an analog of MH
  • M may be substituted with Cys (C)
  • H (His) is Y (Tyr).
  • F (Phe) or W (Trp) may be substituted.
  • Both analogs of M and H may be substituted, but it is more preferable that only one of them is substituted.
  • Preferred active ingredients of the present invention are MH, MY, MF, MW, HM, YM, FM or WM.
  • the peptide which is an active ingredient of this invention may be used independently, and may use 2 or more types of peptides together.
  • the amino acids constituting the peptide are L-form amino acids, D-form amino acids, or DL-form amino acids (the racemate and any amino acid in which either enantiomer is excessive if the D-form and L-form amino acids are mixed). Any of these may be used.
  • Preferable is a peptide consisting only of L-form amino acids or only D-form amino acids, particularly a peptide consisting only of L-form amino acids.
  • the peptide used in the present invention when it contains two or more asymmetric carbons, it may be in the form of each enantiomer or diastereomer or a mixture of these in any ratio. Separation of enantiomers or diastereomers may be carried out using a normal column, or an optically active column is used, or an optically active group is introduced and optically resolved in the form of a derivative, and then the optically active group is removed. Alternatively, any known method such as optical resolution by forming a salt with an optically active acid or base may be used.
  • salts of peptides or analogs thereof include acid addition salts and base salts.
  • Acid addition salts include inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid And salts of organic acids such as benzenesulfonic acid, methanesulfonic acid and trifluoroacetic acid.
  • the base salt include alkali metal salts such as sodium, potassium and lithium, and alkaline earth metal salts such as calcium and magnesium.
  • Solvates include solvates such as water (in the case of hydrates), methanol, ethanol, isopropanol, acetic acid, tetrahydrofuran, acetone, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetamide, ethylene glycol, propylene glycol, and dimethoxyethane. Things.
  • the peptide of the present invention can be obtained by hydrolysis of a natural protein (particularly ⁇ -lactoglobulin) or polypeptide, or by chemical synthesis.
  • the protein or polypeptide to be hydrolyzed includes the dipeptide sequence of the present invention, which is contained in a large amount of whey protein derived from mammalian milk (particularly whey protein), such as milk.
  • Milk-derived ⁇ -lactoglobulin is particularly preferred as a source of the active ingredient peptide of the present invention.
  • These peptides derived from food materials can be used as they are, or as they are, as they are, by performing treatments such as concentration, desalting and purification as necessary.
  • Examples of protein hydrolysis include the use of hydrolytic enzymes derived from animals, plants, or microorganisms such as trypsin, chymotrypsin, papain, pepsin, carboxypeptidase, and thermolysin.
  • the peptide of the active ingredient of the present invention can be obtained by adjusting to an appropriate value and reacting at a temperature of about 30 to 40 ° C. for about 30 minutes to 48 hours.
  • the peptide of the present invention may be purified from the obtained reaction solution, and when the food material is enzymatically decomposed, it can be used as it is or added to another food material to form a food or a food composition.
  • the hydrolase is preferably an enzyme that can be used as a food, such as mammals such as cattle and pigs, and microorganisms that can be used as food (food yeast such as baker's yeast and brewer's yeast).
  • Hydrolysis can be performed using strong acids (for example, hydrochloric acid, nitric acid, sulfuric acid, etc.) or strong bases (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, carbonates).
  • strong acids for example, hydrochloric acid, nitric acid, sulfuric acid, etc.
  • strong bases alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, carbonates.
  • the peptide of the active ingredient of the present invention can be obtained by reacting in water at a temperature of 1 to 100 ° C. for 30 minutes to 48 hours in the presence of an alkali metal hydrogen carbonate such as sodium hydrogen or potassium hydrogen carbonate). It can.
  • the reaction product of the hydrolysis may be used as it is after the pH is adjusted, or the peptide of the active ingredient may be separated and used by purification.
  • the peptide of the present invention can also be obtained by peptide synthesis. That is, in a liquid phase method or a solid phase method, which is a commonly used method for peptide synthesis, a method using an active ester such as HBTU, a raw material having a reactive carboxyl group and a raw material having a reactive amino group, or carbodiimide In a peptide synthesis such as a method using a coupling agent such as When the resulting condensate has a protecting group, it can also be produced by removing the protecting group.
  • the C-terminal carboxyl group is a chlorotrityl resin, chloromethyl resin, oxymethyl resin, p- It is bound to a carrier such as an alkoxybenzyl alcohol resin.
  • the condensation reaction is carried out in the presence of a condensing agent such as carbodiimide or using an N-protected amino acid active ester or peptide active ester.
  • the protecting group is removed, but in the case of the solid phase method, the bond between the C-terminus of the peptide and the resin is further cleaved.
  • the peptides of the present invention are purified according to conventional methods. Examples thereof include ion exchange chromatography, reverse phase liquid chromatography, affinity chromatography and the like. Synthesis of the synthesized peptide is analyzed by a protein sequencer that reads the amino acid sequence from the C-terminal by the Edman degradation method, GC-MS, or the like.
  • the peptide of the present invention can also be synthesized by an enzymatic method (see WO2003 / 010307).
  • the administration route of the peptide of the present invention is not particularly limited, and any of oral administration, parenteral administration, and rectal administration can be adopted, and it can be administered orally or parenterally.
  • the dose of this peptide varies depending on the type of compound, the method of administration, the condition and age of the person being administered, etc., but is usually 0.01 mg / kg to 500 mg / kg, preferably 0.05 mg / kg 100 mg / kg, more preferably 0.1-30 mg / kg.
  • the peptide (active ingredient) of the present invention is usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
  • a pharmaceutical carrier a substance that is commonly used in the pharmaceutical field and does not react with the peptide of the present invention is used.
  • the peptide of the present invention can be used as a food or a medicine per se, or alone or together with a suitable non-toxic carrier for ingestion, diluent or excipient (tablet, uncoated tablet, dragee, effervescent tablet, Film-coated tablets, chewable tablets, etc.), capsules, troches, powders, fine granules, granules, solutions, suspensions, emulsions, pastes, creams, injections (amino acid infusions, electrolyte infusions, etc.) Or a preparation for food or medicine such as sustained release preparations such as enteric tablets, capsules and granules.
  • the content of the peptide in the food can be appropriately selected, but is generally in the range of 0.01 to 100% by weight.
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections, and the like. These preparations are prepared according to a conventional method.
  • the liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method.
  • injection it is prepared by dissolving the peptide of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good.
  • These preparations may contain the peptide of the present invention in a proportion of 0.01% to 100% by weight, preferably 1 to 90% by weight. These formulations may also contain other therapeutically valuable ingredients.
  • an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules.
  • these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate or talc.
  • granules or tablets should be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation, or with ethylcellulose, carnauba wax, hardened oil, etc. You can also.
  • an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation, or with ethylcellulose, carnauba wax, hardened oil, etc. You can also.
  • powders or granules are filled into hard capsules, or active ingredients are dissolved as they are or dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc., and then coated with a gelatin film to form soft capsules. Can do.
  • an active ingredient and a sweetener such as sucrose, sorbitol, and glycerin are dissolved in water to add a transparent syrup, further essential oil, ethanol, etc. to make an elixir, Gum arabic, tragacanth, polysorbate 80, sodium carboxymethyl cellulose and the like may be added to form an emulsion or suspension.
  • a transparent syrup such as sucrose, sorbitol, and glycerin
  • active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, pH adjusters, sodium chloride, glucose etc. It can be dissolved in distilled water for injection together with an isotonic agent, filtered aseptically and filled into ampoules, or further lyophilized by adding mannitol, dextrin, cyclodextrin, gelatin, etc. .
  • reticin, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like may be added to the active ingredient and emulsified in water to give an emulsion for injection.
  • the active ingredient is moistened with a suppository base such as cacao butter, fatty acid tri, di and monoglycerides, polyethylene glycol, etc., poured into a mold and cooled,
  • a suppository base such as cacao butter, fatty acid tri, di and monoglycerides, polyethylene glycol, etc.
  • the active ingredient may be dissolved in polyethylene glycol, soybean oil, etc. and then covered with a gelatin film.
  • the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to make an ointment, or rosin, alkyl acrylate polymer After being kneaded with an adhesive such as polyalkyl, it is spread on a non-woven fabric such as polyalkyl to obtain a tape.
  • beverages coffee, cocoa, juice, soft drinks, mineral drinks, tea drinks, green tea, tea, oolong tea, and milk drinks.
  • Lactic acid bacteria drink yogurt drink, carbonated drink
  • gum gummi
  • jelly candy
  • cookies crackers
  • biscuits ice confectionery (ice cream, ice candy, sorbet, shaved ice, etc.)
  • retort food jelly-like food (je
  • Examples of foods that can be prepared by adding and blending the peptides of the present invention include so-called health foods, functional foods, dietary supplements, supplements, foods for specified health use, foods for sick people and combination foods for sick people (Ministry of Health, Labor and Welfare, It may be a special-use food) or aged food (Ministry of Health, Labor and Welfare, a special-use food), including uncoated tablets, film-coated tablets, sugar-coated tablets, granules, powders, tablets, and capsules (including both hard capsules and soft capsules) .), Chewable type, syrup type, drink type, etc.
  • the preparation of food containing the peptide according to the present invention can be carried out by a method known per se.
  • the elevated plus maze (EPM) consists of two open arms (25cm x 5cm) and two closed arms (25cm x 5cm x 15cm), which are 50cm from the floor. Combined with the raised central platform (see FIG. 1). Despite being in a high position, the mouse can safely walk because of the enclosure around the closed arm. On the other hand, since the periphery of the open arm is open and there is no enclosure, the mouse walking on the open arm feels uneasy that the mouse falls from a high position. For this reason, the longer the mouse stays in the open arm or the greater the number of times of entry, the less the anxiety of the mouse, which becomes an index of anxiolytic activity.
  • the test was started by placing the mouse on the central platform facing one of the open arms. Cumulative time spent in open arms (time in open arms), number of visits to open arms (visit to open arms), total number of visits to any arm (total visits) was recorded. The percentage of time spent in the open arm and the percentage of visits to the open arm were calculated as an indicator of anxiety.
  • the peptide as the active ingredient of the present invention was administered to mice 3 hours before insulin administration, insulin was administered 3 hours later, 15 minutes, 30 minutes later, 60 minutes after insulin administration. The blood glucose level was measured after a minute.
  • MH was found to show an anxiolytic effect even when administered orally, and its minimum effective dose was 1 mg / kg.
  • MH administration (0.1 mg / kg, ip) ⁇ showed a tendency to increase the stay time of the central circle, which is considered to show a strong anxiolytic effect in multiple evaluation systems. It is done.
  • the experimental animal was a male ddY mouse (21-28 g), and the test was started 30 minutes after administration, and the behavior was observed for 5 minutes.
  • an anxiolytic activity was evaluated by increasing the percentage of staying time in the open arm using a cross maze with a height of 50 cm, consisting of a closed arm with a wall and an open arm without a wall.
  • the enzyme digest was fractionated by reversed-phase HPLC, and the anxiolytic activity of each fraction was measured.
  • the peptide of fraction A in which activity was recognized was identified with a protein sequencer and a mass spectrometer, and the anti-anxiety activity was further examined for those chemically synthesized based on the sequence.
  • the peptide with strong anxiolytic activity was MH.
  • Example 4 The effect of the peptide MH of the present invention on insulin sensitivity was tested. Specifically, an insulin tolerance test shown in FIG. 11 was performed, and blood glucose levels were measured 15 minutes, 30 minutes, and 60 minutes after insulin administration. The results are shown in FIG.
  • FIG. 12 shows that the peptide of the present invention can enhance insulin sensitivity. Increased insulin resistance is a serious problem for diabetic patients, and the peptides of the present invention are excellent as supplements, foods, and medicines for insulin patients.
  • MH peptide was found to significantly enhance the blood glucose lowering effect of insulin when administered intraperitoneally to mice (1 mg / kg).
  • the peptide of the present invention can simultaneously suppress anxiety, there are many stresses in humans, pets (dogs, cats, etc.), livestock (cattle, pigs, sheep, etc.), lack of exercise, insulin resistance, and lifestyle Useful in mammals where disease is a problem.
  • the insulin tolerance test has been found to be in good agreement with the results obtained in long-term administration experiments in obese / diabetic model animals, and the energy metabolism improving action of the peptide of the present invention can be expected.
  • Example 5 We investigated the effect of MH administration on the expression of neural activity markers in the brain.
  • physiological saline and MH (1 mg / kg) were administered intraperitoneally, and after 60 minutes, the abdomen was opened and perfusion was fixed with a 4% paraformaldehyde solution.
  • Anesthesia was performed by intraperitoneally administering pentobarbital 5 minutes before laparotomy.
  • the brain samples were immersed in a 4% paraformaldehyde solution at room temperature daily and then dehydrated in a 20% sucrose solution (4 ° C.) for 2 days.
  • frozen sections of brain samples were immunostained with anti-c-Fos antibody, and changes in c-Fos expression in the hippocampus were observed.
  • the number of c-Fos expressing cells in the control group to which physiological saline was administered was 47, but increased to 84 after MH administration. Therefore, it is considered that the nerve activity in the hippocampus is increased, and MH can be expected to have an antidepressant action in addition to an anxiolytic action.

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Abstract

La présente invention concerne un produit pharmaceutique, une composition pharmaceutique, ou un aliment dans lequel un dipeptide comprenant un Met (M) ou un analogue de celui-ci et un His (H) ou un analogue de celui-ci est un principe actif, ainsi qu'un procédé et son utilisation pour la prévention ou le traitement d'une maladie telle qu'une maladie liée au mode de vie.
PCT/JP2013/054289 2012-03-02 2013-02-21 Produit pharmaceutique ou aliment contenant un peptide WO2013129220A1 (fr)

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WO2016190395A1 (fr) * 2015-05-27 2016-12-01 キリン株式会社 Composition de suppression d'inflammation comprenant un peptide
WO2017150536A1 (fr) * 2016-02-29 2017-09-08 国立大学法人京都大学 Peptide
JP2017165661A (ja) * 2016-03-14 2017-09-21 雪印メグミルク株式会社 糖質代謝改善剤
US10434133B2 (en) 2015-05-27 2019-10-08 Kirin Holdings Kabushiki Kaisha Inflammation-suppressing composition including peptide
WO2019216307A1 (fr) 2018-05-08 2019-11-14 国立大学法人京都大学 Peptide, composition, et méthodes de traitement, de prévention ou d'atténuation d'un trouble de l'humeur
WO2023100758A1 (fr) * 2021-11-30 2023-06-08 国立大学法人京都大学 Composition contenant un peptide

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JP2015208282A (ja) * 2014-04-28 2015-11-24 不二製油株式会社 脳神経疾患の予防又は脳機能改善用食品を製造するための食品添加物
CN106231925A (zh) * 2014-04-28 2016-12-14 不二制油集团控股株式会社 用于制造预防脑神经疾病或改善脑功能用食品的食品添加剂
WO2015166938A1 (fr) * 2014-04-28 2015-11-05 不二製油グループ本社株式会社 Additif alimentaire pour la production de produits alimentaires permettant de prévenir une neuropathie crânienne et/ou d'améliorer la fonction cérébrale
US10434133B2 (en) 2015-05-27 2019-10-08 Kirin Holdings Kabushiki Kaisha Inflammation-suppressing composition including peptide
WO2016190395A1 (fr) * 2015-05-27 2016-12-01 キリン株式会社 Composition de suppression d'inflammation comprenant un peptide
AU2016268710B2 (en) * 2015-05-27 2021-12-09 Kirin Holdings Kabushiki Kaisha Inflammation-suppressing composition including peptide
WO2017150536A1 (fr) * 2016-02-29 2017-09-08 国立大学法人京都大学 Peptide
JPWO2017150536A1 (ja) * 2016-02-29 2018-12-27 国立大学法人京都大学 ペプチド
JP2017165661A (ja) * 2016-03-14 2017-09-21 雪印メグミルク株式会社 糖質代謝改善剤
WO2019216307A1 (fr) 2018-05-08 2019-11-14 国立大学法人京都大学 Peptide, composition, et méthodes de traitement, de prévention ou d'atténuation d'un trouble de l'humeur
CN112074529A (zh) * 2018-05-08 2020-12-11 国立大学法人京都大学 肽、组合物及治疗、预防或改善心境障碍的方法
KR20210005150A (ko) 2018-05-08 2021-01-13 고쿠리츠 다이가쿠 호진 교토 다이가쿠 펩타이드, 조성물 및 기분장애를 치료, 예방, 또는 개선하는 방법
EP3816178A4 (fr) * 2018-05-08 2021-08-18 Kyoto University Peptide, composition, et méthodes de traitement, de prévention ou d'atténuation d'un trouble de l'humeur
KR20230125847A (ko) 2018-05-08 2023-08-29 고쿠리츠 다이가쿠 호진 교토 다이가쿠 펩타이드, 조성물 및 기분장애를 치료, 예방, 또는개선하는 방법
CN112074529B (zh) * 2018-05-08 2023-10-13 国立大学法人京都大学 肽、组合物及治疗、预防或改善心境障碍的方法
WO2023100758A1 (fr) * 2021-11-30 2023-06-08 国立大学法人京都大学 Composition contenant un peptide

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