CN112020366A - Pharmaceutical composition containing dipeptide - Google Patents
Pharmaceutical composition containing dipeptide Download PDFInfo
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- CN112020366A CN112020366A CN201980028106.3A CN201980028106A CN112020366A CN 112020366 A CN112020366 A CN 112020366A CN 201980028106 A CN201980028106 A CN 201980028106A CN 112020366 A CN112020366 A CN 112020366A
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
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Abstract
The present invention provides a novel anti-inflammatory agent. The anti-inflammatory agent of the present invention is selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) e- (L) Hyp, and, (D) Dipeptides among Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
Description
Technical Field
The present invention relates to a pharmaceutical or food composition containing a dipeptide.
Background
In the aging society, there is an increasing importance of measures for preventing and treating lifestyle-related diseases such as diabetes and obesity related to chronic inflammation, and circulatory diseases such as arteriosclerosis. In fact, inhibition of IL-1 β signaling or NF-. kappa.B inhibition was developed for diabetes. In chronic inflammatory diseases such as rheumatoid arthritis, a large amount of inflammatory cytokines such as TNF- α, IL-1 and IL-6 are abnormally produced and secreted, and these inflammatory cytokine suppressors are useful as excellent anti-inflammatory agents. For example, as a TNF- α inhibitor, an antibody drug such as infliximab is used as a therapeutic agent for rheumatoid arthritis (non-patent document 1). In addition, as an IL-6 inhibitor, an antibody drug tollizumab (non-patent document 2) was used. Further, protein preparations such as anakinra, elocept, and canamab, and antibody drugs have been developed as IL-1 inhibitors (non-patent document 3).
Documents of the prior art
Non-patent document
Non-patent document 1: TNF inhibitory drug guidelines for Rheumatoid Arthritis (RA) (Japan society of general law)
Non-patent document 2: pharmaceutical journal 129(6)667-674(2009)
Non-patent document 3: journal of Japan medical Association 100, volume 10, p.2985-2990(2011, 10 months and 10 days)
Disclosure of Invention
Under such circumstances, the present inventors have found that a liver hydrolysate has an excellent inhibitory effect on the production of IL-1 and is useful as a cytokine production inhibitor and an anti-inflammatory agent, and have previously made a patent application (PCT/JP 2018/006351).
However, the liver hydrolysate contains a large amount of amino acids and peptides, but the actual active ingredients have not been known.
Accordingly, an object of the present invention is to provide a novel anti-inflammatory agent based on an inhibitory effect on cytokine production.
Accordingly, the present inventors have conducted studies to develop a novel anti-inflammatory agent, and as a result, have found that a dipeptide derived from a specific D-body amino acid, not from an L-body amino acid, and that the dipeptide has an inhibitory effect on cytokine production such as IL-1 β and IL-6, by administering a liver hydrolysate to an animal, searching for indigestible peptides that are transported to the blood, and fractionating the peptides using various columns for the liver hydrolysate, and evaluating the drug efficacy.
Namely, the present invention provides the following [1] to [15 ].
[1] An anti-inflammatory agent selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) e- (L) Hyp, and, (D) Dipeptides among Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
[2] The anti-inflammatory agent according to [1], wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[3] An inflammatory cytokine production inhibitor selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Glu, (D) Ile- (D) pGlu, (D) Val- (D) pGlu, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) Dipeptides among Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
[4] The inhibitor of inflammatory cytokine production according to [3], wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[5] An IL-1 production inhibitor or IL-6 production inhibitor selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are active ingredients.
[6] The IL-1 production inhibitor or IL-6 production inhibitor according to [5], wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (L) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[7] A food composition for ameliorating inflammation, which is selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) Dipeptides among Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
[8] The food composition according to [7], wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[9] An inflammatory cytokine production-suppressing food composition comprising a peptide selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are active ingredients.
[10] The food composition according to [9], wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[11] A food composition for inhibiting IL-1 production or a food composition for inhibiting IL-6 production, which is selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Glu, (D) Ile- (D) pGlu, (D) Val- (D) pGlu, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Pro- (L) -Pro, (D) Pro- (L) Val, Val- (L) Val, (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are active ingredients.
[12] The food composition according to [11], wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[13] Use of a dipeptide selected from (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, for the manufacture of an anti-inflammatory agent, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[14] A dipeptide selected from (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Glu, (D) Ile- (D) pGlu, (D) Val- (D) pGlu, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, Val- (L) Pro, and, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
[15] A method for treating an anti-inflammatory disease, which comprises administering an effective amount of an agent selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val), (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu, and (D) Asp- (L) Phe.
The dipeptide used in the present invention is indigestible due to its D-body amino acid origin, has an IL-1 production inhibitory activity and an IL-6 production inhibitory activity for a long period of time in blood, and is therefore useful as a drug or food composition for inhibiting cytokine production and for resisting inflammation.
Drawings
FIG. 1 shows the inhibition of IL-6 production by hydrophobic peptide fractions.
FIG. 2 shows the IL-6 production inhibition by the hydrophobic pyroglutamyl peptide fraction.
FIG. 3 shows the IL-6 production inhibition by the hydrophilic peptide fraction.
FIG. 4 shows the IL-6 production inhibition by the hydrophilic pyroglutamyl peptide fraction.
FIG. 5 shows the IL-1. beta. production inhibition by the hydrophobic peptide fraction.
FIG. 6 shows the IL-1. beta. production inhibitory effect of the hydrophobic pyroglutamyl peptide fraction.
Detailed Description
The dipeptide as the active ingredient of the anti-inflammatory agent of the present invention is selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) Dipeptides of Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are preferably dipeptides selected from (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe, and more preferably (D) Asp- (D) Leu and (D) Asp- (L) Leu, from the viewpoints of transportability to the blood, duration of action and anti-inflammatory action upon oral administration.
The expression (D) means that the amino acid is in the D form. The expression (L) means that the amino acid is in the L form.
Among the α -and β -forms of the dipeptide of the above-mentioned (D) form or (L) form, the β -form is more preferable.
The dipeptide can be produced by a general liquid phase peptide synthesis method or a solid phase peptide synthesis method using the amino acid (D) as a raw material. For example, the production can be carried out by the following method: the protecting group is removed by condensing an amino acid having a functional group other than an α -amino group protected with an amino acid having a functional group other than a carboxyl group activated with an amino acid having a functional group other than a carboxyl group protected with an amino acid.
Examples of the protective group for an amino group of an amino acid include a benzyloxycarbonyl group, a tert-butoxycarbonyl group, and a fluorenylmethoxycarbonyl group. Examples of the protecting group of the carboxyl group include a tert-butyl group and a benzyl group. The condensation reaction can be carried out by a method using N, N' -dicyclohexylcarbodiimide, dicyclohexylurea or other condensing agents, an active ester method using nitrophenol, N-hydroxysuccinimide or the like, a mixed acid anhydride method or the like.
After the condensation reaction is completed, the protecting group is removed, but in the case of the solid phase method, the bond between the C-terminal of the peptide and the resin is further cleaved. Further, the peptide is purified by a usual method.
The above-mentioned dipeptides may be acid addition salts or basic salts. Examples of the acid addition salts include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and perchloric acid; salts of organic acids such as citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. Examples of the basic salt include alkali metal salts such as sodium, potassium, and lithium; and salts of alkaline earth metals such as calcium and magnesium.
The peptide may be a solvate. Examples of the solvate include water (in the case of a hydrate), and solvates such as methanol, ethanol, and isopropanol.
The dipeptide has indigestibility, high blood transportability after oral administration, excellent persistence, and strong inhibitory activity against the production of IL-1. beta. and IL-6, which are one of inflammatory cytokines, and inhibitory activity against the expression of mRNA of IL-1. beta. and IL-6. Therefore, the above-mentioned dipeptide inhibits the production of inflammatory cytokines such as IL-1 and IL-6, and is useful as a therapeutic agent for inflammatory diseases associated with inflammatory cytokines and a food or beverage composition for ameliorating inflammation. Examples of diseases associated with inflammatory cytokines such as IL-1 and IL-6 include rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, acute and chronic bone marrow leukemia, osteoporosis, and lifestyle-related diseases.
The pharmaceutical composition of the present invention can be administered by oral administration, transdermal administration, intestinal administration, intravenous administration, etc., more preferably oral administration. Examples of the preparation for oral administration include a liquid, a tablet, a powder, a fine granule, a capsule, etc., and the liquid and the tablet are preferable, and the liquid is more preferable.
To prepare these oral administration preparations, excipients such as lactose, mannitol, corn starch, crystalline cellulose, and the like; binders such as cellulose derivatives, gum arabic, and gelatin; disintegrating agents such as calcium carboxymethylcellulose; lubricants such as talc and magnesium stearate; dissolution aids such as nonionic surfactants; flavoring agent, sweetener, stabilizer, pH regulator, water, ethanol, propylene glycol, glycerol, etc. Coating agents such as hydroxymethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymers may also be used.
In addition, other active ingredients may be incorporated into the pharmaceutical composition of the present invention. As other active ingredients, vitamin B may be mentioned1Class; thiamine, thiamine nitrate, thiamine hydrochloride, furthiamine, bisbentiamine, benfotiamine, thiamine disulfide, thiamine propyl disulfide, derivatives thereof, vitamin B2Class; riboflavinAnd derivatives and their salts, vitamin B3Class; nicotinic acid, nicotinamide and derivatives and their salts, vitamin B5Class; panthenol, pantothenic acid and derivatives, salts thereof, and vitamin B6Class; pyridoxine and derivatives and their salts, vitamin B12Class; cyanocobalamin and derivatives and their salts, other vitamins; vitamin a, vitamin C, vitamin E, vitamin K, vitamin P, diisopropylamine dichloroacetate, taurine, chondroitin sulfate, royal jelly, caffeine, turmeric, silybum marianum, dandelion, burdock, garlic, chrysanthemum, yarrow, gardenia, sesame, pseudo-ginseng, asparagus cochinchinensis, onion, chicory, common sage herb, artichoke (artichoke), medlar, a plant of leguminosae and iridaceae, zebra, shrub (Erva De Passarinho), balsam cuphea, mallotus japonicus, black tea, resveratrol, catechins, berberine, rosemary, bean extract, metformin, and the like.
In addition, the composition of the present invention can be used as a functional food such as a quasi drug, a specific health food, a sports drink, a rehabilitation drink, a pet food, and the like, in addition to a drug.
The content of the dipeptide in the pharmaceutical composition or food composition of the present invention varies depending on the form of administration, and is preferably 0.001 to 10% by mass, and more preferably 0.001 to 5% by mass. The amount of the dipeptide administered in the pharmaceutical composition or food composition of the present invention in 1 day is preferably 10mg to 1000mg, more preferably 20mg to 800mg, and still more preferably 50mg to 800 mg.
Examples
The present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.
Example 1 (grading of liver hydrolysates)
(1) Fractionation of peptides and pyroglutamyl peptides
A strong cation exchange resin (AG50) was packed in Econo Column (2.5X 20cm) and the resin was equilibrated with 10mM HCl. 1g of liver hydrolysate (sample A) was dissolved in 20mL of 10mM HCl. This solution was added to the resin and 20mL of flow-through fraction (flow-through fraction 1) was recovered. Next, 20mL of 10mM HCl was added to the resin and 20mL of the flow-through fraction was recovered. This operation was repeated 19 times (flow through fractions 2 to 20). The absorbance (230nm) of the fractions 1 to 20 was measured to confirm the elution of the peptide.
Subsequently, 20mL of 50% ammonia solution was added to the resin, and 20mL of the adsorbed fraction was recovered. This operation was repeated 20 times (adsorption fractions 1 to 20). The absorbance (230nm) of the adsorbed fractions 1 to 20 was measured to confirm the elution of the peptide.
The flow-through fraction (pyroglutamyl peptide fraction) and the adsorption fraction (peptide fraction) were concentrated under reduced pressure using an evaporator.
(2) Grading of hydrophilicity and hydrophobicity
The solid phase extraction column (Sep-Pak) was equilibrated with 10mM HCl. The pyroglutamyl peptide fraction was passed through a column, and the flow-through fraction was eluted and recovered (hydrophilic pyroglutamyl peptide fraction). Subsequently, a 60% acetonitrile solution containing 10mM HCl was passed through the column, and the adsorbed fraction was eluted and recovered (hydrophobic pyroglutamyl peptide fraction).
These operations were also performed on the peptide fraction.
The 4 fractions obtained were freeze-dried.
Example 2
(1) Quantitative assay for indigestible peptides in liver hydrolysates
1) 2.5mg of liver hydrolysate was dissolved in 1mL of 50mM Tris-HCl.
2) Pancreatin (0.1mg), leucine aminopeptidase (2.45unit) and carboxypeptidase (7.7unit) were added to 1) to carry out an enzymatic reaction (37 ℃ C., 24 hours).
3) The enzyme was removed by ultrafiltration (10K).
4) Passing 3) through a strong cation exchange resin (AG50) packed in a spin column, and recovering the flow-through fraction (pyroglutamyl peptide fraction).
5) 200 μ L of 3) (peptide fraction) and 4) (pyroglutamyl peptide fraction) (SEC Fr.35-44) were fractionated by size exclusion HPLC and fractionated.
6) SEC Fr.35-44 was dried for peptide fractions and accQ was performed. SEC Fr.35-44 was used directly for the pyroglutamyl peptide fraction.
7) The structure of the indigestible peptide was determined by LC-MS/MS analysis.
Column: inertsil ODS-3
Eluent: 0.1% formic acid and 80% acetonitrile containing 0.1% formic acid
The analysis method comprises the following steps: after a fragment (m/z 171.1) of AccQ was specifically detected (precarsor ion scan analysis) in the peptide fraction, the structure was estimated by MS/MS analysis, and a standard was synthesized, and identified and quantified by MRM analysis.
After a peak was detected by Total scan analysis for the pyroglutamyl peptide fraction, a structure was estimated by MS/MS analysis, and a standard product was synthesized and identified and quantified by MRM.
(2) Experiment of peptide transport in blood when liver hydrolysate was administered to rat
1) A single dose of aqueous liver hydrolysate (10g/60kg) was administered to Uster rats (6 weeks old, male).
2) After 30 and 60 minutes of administration, blood was collected from the abdominal vena cava under isoflurane anesthesia to obtain plasma. The digestive tract (duodenum-ileum) was then removed, and the contents of the lumen were dissolved in 10mL of physiological saline. To the plasma and gut contents was added 3-fold amount of ethanol (stored at-20 ℃ C. prior to analysis).
3) The ethanol supernatant of the plasma and the contents of the digestive tract were dried and AccQ-treated.
4) Identification and quantification of the indigestible peptide identified in (1) by MRM analysis.
The dipeptide concentration in blood is shown in Table 1.
[ Table 1]
(pmolmL)
(min) | Asp-Leu(Dα) | Asp-Val(Dα) | Asp-Ile(Dα) | Asp-Phe(Dα) |
0 | 2.03±0.94 | ND | 2.03±0.94 | 0.09±0.16 |
60 | 16.43±2.09** | 8.84±0.85** | 16.43±2.10** | 2.08±0.09** |
(min) | Asp-Leu(Dβ) | Asp-Val(Dβ) | Asp-Ile(Dβ) | Asp-Phe(Dβ) |
0 | 3.41±0.50 | ND | 3.56±1.28 | 1.54±0.62 |
60 | 28.54±2.83** | 16.31±3.27* | 26.37±2.66** | 17.67±3.25** |
Average (n ═ 3) ± SD ≦ 0.05, and ≦ 0.01
Asp-Leu (D α), Asp-Val (D α): Asp-Leu cannot be separated in LC, and therefore,
are all Asp-Ile + Asp-Leu (D alpha)
As a result, it was found that (D) Asp- (D) Val, (D) Asp- (D) Phe, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu, and (D) Asp- (L) Phe had good blood transportability by oral administration and continued for a long period of time in the blood.
Example 3 (Synthesis of dipeptide)
1) The reagents were added to an eggplant type flask in the following order, and the reaction was carried out while stirring (4 ℃ C., overnight).
(i)H-Leu-OtBu·HCl
(ii)DMF
(iii)TEA
(iv) Boc-Asp (OtBu) -OH (L.alpha.body)
(v)HOBt
(vi)EDL·HCl
In the case of the other isomers, the following protected amino acids were used.
Boc-D-Asp (OtBu) -OH (D.alpha.body)
Boc-Asp-OtBu (L beta body)
Boc-D-Asp-OtBu (D β form)
2) DMF was removed using an evaporator.
3) Dissolved in ethyl acetate and transferred to a separatory funnel.
4) 5% sodium bicarbonate was added and stirred, and the aqueous layer was removed. (. times.2)
5) 10% citric acid was added and stirred, and the aqueous layer was removed. (. times.2)
6) Saturated brine was added and stirred, and the aqueous layer was removed.
7) The ethyl acetate layer was recovered, and sodium hydrogensulfate was added to dehydrate the ethyl acetate layer.
8) The ethyl acetate layer was recovered by filtration and concentrated by an evaporator.
9) Petroleum ether was added and the resulting precipitate was dried. (proceed to 10 without precipitation)
12) Diethyl ether was added, the resulting precipitate was broken and washed with ultrasound, and the ether supernatant was removed with decane. (. times.3)
13) Ether was added and left to stand (4 ℃, overnight).
14) Diethyl ether was added, the resulting precipitate was broken and washed with ultrasound, and the ether supernatant was removed with decane. (. times.3)
15) The precipitate was dried.
Example 4
The number of cells in RAW264.7 cells was adjusted to 1.5X 106cells/dish were inoculated and cultured evening-out. The pre-fractionated sample or filtrate fractions were diluted 20-fold together in EMEM medium (final concentration about 0.6 mg/mL). As a control, PBS was diluted 20-fold in EMEM medium instead of samples. Each of the samples (control, pre-fractionation, filtrate fraction) diluted in the culture medium was added to each dish group. After 24 hours of incubation, Lipopolysaccharide (LPS) was added so that the final concentration became 1.0. mu.g/mL. Standing for 3 hoursRNA was recovered and cDNA synthesis was performed by reverse transcription. Then, EEF1A1 and IL-6 were measured by RT-RCR.
The results are shown in FIGS. 1 to 4.
In the RAW cells stimulated with LPS, the mRNA expression levels of the inflammation-related genes were compared between the dipeptide group and the control group to which PBS was added instead of the dipeptide, and as a result, IL-6 was significantly reduced in the hydrophobic peptide fraction and the hydrophobic pyroglutamyl peptide fraction, indicating the inflammation inhibitory effect of the dipeptide.
Example 5
The number of cells in RAW264.7 cells was adjusted to 1.5X 106cells/dish were inoculated and cultured evening-out. The pre-fractionated sample or filtrate fractions were diluted 20-fold together in EMEM medium (final concentration about 0.6 mg/mL). As a control, PBS was diluted 20-fold in EMEM medium instead of samples. Each of the samples (control, pre-fractionation, filtrate fraction) diluted in the culture medium was added to each dish group. After 24 hours of incubation, Lipopolysaccharide (LPS) was added so that the final concentration became 1.0. mu.g/mL. After standing for 3 hours, RNA was recovered and cDNA synthesis was performed by reverse transcription. Then, EEF1A1 and IL-1. beta. were measured by RT-RCR.
The results are shown in fig. 5 to 6.
In the RAW cells stimulated with LPS, the mRNA expression levels of inflammation-related genes were compared between the dipeptide group and the control group to which PBS was added instead of the dipeptide, and as a result, IL-1 β was significantly reduced in the hydrophobic peptide fraction, indicating the inflammation inhibitory effect of the dipeptide.
Claims (15)
1. An anti-inflammatory agent selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) Dipeptides among Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
2. An anti-inflammatory agent according to claim 1, wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
3. An inflammatory cytokine production inhibitor selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) Dipeptides among Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
4. The inflammatory cytokine production inhibitor according to claim 3, wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
5. An IL-1 production inhibitor or IL-6 production inhibitor selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are active ingredients.
6. The IL-1 production inhibitor or IL-6 production inhibitor according to claim 5, wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
7. A food composition for ameliorating inflammation, which is selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, (D) Dipeptides among Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are effective components.
8. The food composition according to claim 7, wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
9. An inflammatory cytokine production-suppressing food composition comprising a peptide selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are active ingredients.
10. The food composition according to claim 9, wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
11. A food composition for inhibiting IL-1 production or a food composition for inhibiting IL-6 production, which is selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Glu, (D) Ile- (D) pGlu, (D) Val- (D) pGlu, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Pro- (L) -Pro, (D) Pro- (L) Val, Val- (L) Val, (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe are active ingredients.
12. The food composition according to claim 11, wherein the active ingredient is selected from the group consisting of (D) Asp- (D) Val, (D) Asp- (D) Ile, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Asp- (L) Val, (D) Asp- (L) Ile, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
13. Use of a dipeptide selected from (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, for the manufacture of an anti-inflammatory agent, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
14. A dipeptide selected from (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) Pro, (D) Pro- (D) Val, (D) Leu- (D) Glu, (D) Ile- (D) pGlu, (D) Val- (D) pGlu, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val, (D) Leu- (L) Hyp, Val- (L) Pro, and, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu and (D) Asp- (L) Phe.
15. A method for treating an anti-inflammatory disease, which comprises administering an effective amount of an agent selected from the group consisting of (D) Ile- (D) Pro, (D) Leu- (D) Pro, (D) Pro- (D) Ile, (D) Pro- (D) Leu, (D) Val- (D) -Pro, (D) Pro- (D) Val, (D) Leu- (D) Hyp, (D) Ile- (D) Hyp, (D) Val- (D) Hyp, (D) Asp- (D) Ile, (D) Asp- (D) Val, (D) Asp- (D) Leu, (D) Asp- (D) Phe, (D) Ile- (L) Pro, (D) Leu- (L) Pro, (D) Pro- (L) Ile, (D) Pro- (L) Leu, (D) Val- (L) -Pro, (D) Pro- (L) Val), (D) Dipeptides among Leu- (L) Hyp, (D) Ile- (L) Hyp, (D) Val- (L) Hyp, (D) Asp- (L) Ile, (D) Asp- (L) Val, (D) Asp- (L) Leu, and (D) Asp- (L) Phe.
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CN102224161A (en) * | 2008-09-22 | 2011-10-19 | 日清药业股份有限公司 | Antiinflammatory peptide |
WO2016190395A1 (en) * | 2015-05-27 | 2016-12-01 | キリン株式会社 | Inflammation-suppressing composition including peptide |
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US6126939A (en) * | 1996-09-03 | 2000-10-03 | Yeda Research And Development Co. Ltd. | Anti-inflammatory dipeptide and pharmaceutical composition thereof |
WO2018155525A1 (en) * | 2017-02-23 | 2018-08-30 | ゼリア新薬工業株式会社 | Anti-inflammatory agent |
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CN102224161A (en) * | 2008-09-22 | 2011-10-19 | 日清药业股份有限公司 | Antiinflammatory peptide |
WO2016190395A1 (en) * | 2015-05-27 | 2016-12-01 | キリン株式会社 | Inflammation-suppressing composition including peptide |
Non-Patent Citations (2)
Title |
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SHERI M. FUJIHARA等: "A D-Amino Acid Peptide Inhibitor of NF-κB Nuclear Localization Is Eycacious in Models of In|ammatory Disease", THE JOURNAL OF IMMUNOLOGY * |
汪雄;赵燕;徐明生;姚瑶;张梦雅;涂勇刚;: "食源性抗炎肽的制备、分离、鉴定及其抗炎机制研究进展", 食品工业科技 * |
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