WO2017010537A1 - Composition that contains ring-shaped dipeptide and inhibits serum carnosinase - Google Patents

Composition that contains ring-shaped dipeptide and inhibits serum carnosinase Download PDF

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Publication number
WO2017010537A1
WO2017010537A1 PCT/JP2016/070796 JP2016070796W WO2017010537A1 WO 2017010537 A1 WO2017010537 A1 WO 2017010537A1 JP 2016070796 W JP2016070796 W JP 2016070796W WO 2017010537 A1 WO2017010537 A1 WO 2017010537A1
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cyclo
ile
tyr
composition
lys
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PCT/JP2016/070796
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French (fr)
Japanese (ja)
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伸哉 富貴澤
斉志 渡辺
阿部　圭一
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サントリーホールディングス株式会社
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Priority to JP2017528720A priority Critical patent/JP6669750B2/en
Publication of WO2017010537A1 publication Critical patent/WO2017010537A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a composition for inhibiting serum carnosine degrading enzyme. More specifically, the present invention relates to a composition for inhibiting carnosine dipeptidase 1 containing a specific cyclic dipeptide or a salt thereof as an active ingredient, the use of a specific cyclic dipeptide or a salt thereof for inhibiting carnosine dipeptidase 1, carnosine
  • the present invention relates to a method for inhibiting peptidase 1 and a composition comprising a specific cyclic dipeptide or a salt thereof and carnosine.
  • Carnosine is a dipeptide composed of ⁇ -alanine and histidine, and is present in high concentrations in muscle and nerve tissues in mammals such as humans.
  • Carnosine's actions include (1) proton buffering activity, (2) calcium secretion and calcium sensitivity control, (3) antioxidant action, (4) metal ion chelate action, (5) histidine / histamine extracellular donor (6) Hyperglycemia improving action, (7) Anti-inflammatory action, etc. are known.
  • the action of carnosine the production of glycated end products, the suppression of cell death due to cerebral ischemia, the accumulation of amyloid ⁇ in Alzheimer's disease (AD) model mice, the immunoregulatory action, and the like have been reported.
  • AD Alzheimer's disease
  • carnosine contributes to various functions in the body.
  • degradation by carnosine degrading enzyme is a problem for exerting its pharmacological action.
  • CNDP1 carnosine dipeptidase 1
  • CNDP2 tissue carnosinase 2
  • CNDP1 has been shown to exist only in higher primates (human and large monkeys) and not in most other mammals (Non-patent Document 1).
  • Non-patent Document 1 Although these CNDP1 and CNDP2 are highly homologous proteins, their tissue distribution and enzymatic characteristics are different, and both are considered to have different functions.
  • Non-patent Document 2 bestatin is known as an inhibitor (Non-patent Document 2), and others are ⁇ -alanine and linear chains such as Gly-L-His and L-Pro-L-His. It has been reported that dipeptides are effective in inhibiting CNDP2 (Patent Document 1). On the other hand, with regard to CNDP1, for example, phenanthroline has been reported as an inhibitor (Non-patent Document 3), but there are few known carnosine degradation inhibitors that focus on inhibition of CNDP1 activity.
  • CNDP1 and CNDP2 are different proteins, the inhibitors for the respective enzymes are also considered to be different from each other.
  • bestatin which is the above CNDP2 inhibitor, has no effect on the inhibition of CNDP1 (Non-patent Document 4).
  • the phenanthroline shown above has CNDP1 inhibitory activity, it is known to show oral toxicity as a side effect thereof. Therefore, if a safer inhibitor of CNDP1 can be found, clinical application to diseases and symptoms related to the activity of CNDP1 is considered possible.
  • CNDP1 in non-patent document 5, in an animal model in which human serum carnosinase (CNDP1) is introduced into a db / db mouse, diabetes, such as fasting blood glucose level and HbA1c are higher than in younger age, indicating weight loss, etc. Admits that symptoms appear. That is, it has been suggested that enhanced carnosine degradation by serum carnosinase (CNDP1) may cause disease onset. Therefore, a composition for inhibiting serum carnosine degrading enzyme (CNDP1) efficiently delivers L-carnosine to plasma, target organs or other organs, and is effective for various diseases caused by diabetes, oxidative stress, and production of advanced glycation end products. It is considered as an approach to increase the preventive effect.
  • Non-Patent Document 6 there is a correlation between a specific gene polymorphism ((CTG) n) in the serum carnosinase (CNDP1) gene and the onset of diabetic nephropathy. It has been reported.
  • Non-Patent Document 7 reports that homozygous (CTG) 5 carriers have a low risk of developing diabetic nephropathy and low serum carnosinase activity. Therefore, suppressing serum carnosinase activity is important for maintaining carnosine concentration, and is considered to be effective in preventing or treating related diseases.
  • CTG specific gene polymorphism
  • Non-Patent Document 8 can be cited as a verification example of a pharmacokinetic test after oral ingestion of carnosine in humans.
  • individual differences in the blood concentration of carnosine at each time after ingestion of carnosine 60 mg / kg are large, and there are some subjects in which no significant increase in blood carnosine concentration was observed compared to before intake (among 25 subjects). 17), the activity of serum carnosinase and the amount of protein were significantly lower in the group in which the increase was observed than in the group in which the increase was not. From this, it is considered that there is a high possibility that suppressing the action of serum carnosinase (CNDP1) is effective in maintaining the blood carnosine concentration.
  • CNDP1 suppressing the action of serum carnosinase
  • CNDP1 exerts various influences in the human body as a mammal, there is a strong demand for highly safe drugs for effectively inhibiting this activity.
  • An object of the present invention is to provide a composition for inhibiting serum carnosine degrading enzyme (CNDP1) that has high biosafety and contributes to maintaining the blood concentration of carnosine.
  • Another object of the present invention is to provide a use of the composition for inhibiting CNDP1, a method for inhibiting CNDP1, and a composition that contributes to maintaining the blood concentration of carnosine with high biosafety. It is in.
  • a cyclic dipeptide is a dipeptide having a cyclic structure formed by dehydration condensation of an amino group and a carboxyl group present at the end of a linear dipeptide.
  • various physiological activities have received attention.
  • the present inventors have intensively studied about a large number of about 200 kinds of cyclic dipeptides composed of combinations of natural amino acids, and found for the first time that a specific cyclic dipeptide has CNDP1 inhibitory activity. Based on this finding, the present inventors have completed the present invention.
  • a composition for inhibiting carnosine dipeptidase 1 comprising, as an active ingredient, a cyclic dipeptide having an amino acid as a structural unit or a salt thereof,
  • the cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine.
  • the composition for inhibiting carnosine dipeptidase 1 according to any one of (1) to (5), which is labeled with a function exhibited by carnosine dipeptidase 1 inhibition.
  • the function display is “suppresses cognitive function decline”, “expects maintenance of cognitive function”, “suppresses increase in blood glucose level”, “improves immune function”, “antioxidant action” ⁇ Expect '', ⁇ Reduce oxidative stress '', ⁇ Expect anti-glycation effect '', ⁇ Reduce glycation stress '', ⁇ Inhibit vascular inflammation '', ⁇ Expect prevention or improvement of Alzheimer's disease '', And the composition according to (6), which is selected from the group consisting of “expecting prevention or improvement of autism”.
  • composition for inhibiting carnosine dipeptidase 1 according to any one of (1) to (7), wherein the composition is an agent.
  • a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for inhibiting carnosine dipeptidase 1 The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine.
  • a method for inhibiting carnosine dipeptidase 1, using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine.
  • a composition having an excellent inhibitory effect on serum carnosine degrading enzyme can be provided.
  • the composition of the present invention By using the composition of the present invention, the effect of delaying degradation of carnosine accompanying the suppression of CNDP1 function can be obtained, so that a higher concentration of carnosine can be efficiently delivered to plasma, target organ or other organs.
  • the composition of the present invention originates from various pharmacological actions that are originally known for carnosine (cognitive decline associated with schizophrenia, diabetes, immune function decline, inflammation of blood vessels and tissues, oxidative stress, etc. It can be effective in improving various diseases onset, prevention of Alzheimer's disease, and autism.
  • the cyclic dipeptide or salt thereof contained as an active ingredient in the composition of the present invention is high in safety because it is also contained in a heat-treated food protein-derived peptide, and side effects are extremely small compared to conventional pharmaceuticals. Conceivable.
  • the cyclic dipeptide is excellent in lipophilicity as compared with the linear dipeptide, and high concentration filling into the oily base material is also possible. Therefore, it can be said that the composition of this invention is excellent in the usability in formulation.
  • cyclic dipeptides are rich in fat solubility and are not dipeptides composed solely of peptide bonds, it is considered that they are resistant to the action of various peptide-degrading enzymes secreted into the digestive tract. Absorbability can also be expected.
  • Carnosine dipeptidase 1 and carnosine dipeptidase 1 inhibition refers to a serotype carnosine degrading enzyme capable of degrading carnosine (L-carnosine) into ⁇ -alanine and histidine.
  • Carnosine dipeptidase (carnosine degrading enzyme) can be abbreviated as CNDP (carnosine dipeptidase), and is also called carnosinase or carnosidase.
  • Carnosine dipeptidase includes CNDP1 which is a serum (type) carnosine degrading enzyme and CNDP2 which is a tissue (type) carnosine degrading enzyme.
  • the carnosine dipeptidase targeted in the present invention is CNDP1, which is distinguished from CNDP2.
  • carnosine dipeptidase 1 inhibition refers to inhibiting the carnosine degradation activity of carnosine dipeptidase 1.
  • the inhibitory action of carnosine dipeptidase 1 can be evaluated according to a known method. For example, when carnosine and carnosine dipeptidase 1 are brought into contact with each other, histidine is generated from carnosine, and histidine-specific fluorescence can be measured due to the presence of histidine. Carnosine dipeptidase can be obtained by examining the decrease in fluorescence intensity. 1 inhibitory action can be evaluated.
  • cyclic dipeptide refers to a cyclic dipeptide having a diketopiperazine structure formed by dehydration condensation of an amino group and a carboxyl group of an amino acid. Say. Therefore, the cyclic dipeptide is distinguished from the chain dipeptide.
  • cyclic dipeptide or its salt may be collectively called a cyclic dipeptide.
  • any order thereof may be used, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)] and Represent the same cyclic dipeptide.
  • cyclic dipeptides In cyclic dipeptides, the terminal portions of two amino acids are linked via an amide bond (that is, the cyclic dipeptide has a cyclic structure formed by the amide bond between the amino terminus and the carboxy terminus. Therefore, cyclic dipeptides are more lipophilic than linear dipeptides with polar carboxyl groups or amino groups exposed at the molecular end (particularly linear dipeptides of the same amino acid composition). It has the characteristics. Therefore, cyclic dipeptides are superior in gastrointestinal permeability and membrane permeability compared to linear dipeptides. This is also clear from the results of compound permeation tests using rat inverted intestinal tracts reported in the past (J. Pharmacol, 1998, 50: 167-172). Cyclic dipeptides are also considered to have increased resistance to various peptidases due to their specific structure.
  • Cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention includes cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucine glutamate [Cyclo (Ile-Glu)], cycloisoleuyl lysine [Cyclo ( Ile-Lys)], cycloleucyl tyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleuyl threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine [ Cyclo (Glu-Leu)], cycloarginyl isoleucine (Cyclo (Arg-Ile)), cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-T
  • cyclic dipeptide or its salt is not specifically limited, In this invention, it is preferable to use 3 or more selected from the cyclic dipeptide mentioned above or its salt as an active ingredient.
  • cyclic dipeptides or salts thereof cyclotryptophanyl tyrosine [Cyclo (Trp-Tyr)], cycloisoleucillysine [Cyclo (Ile-Lys)], cyclophenylalanyltryptophan [Cyclo (Phe- Trp)], cycloisoleucine threonine (Cyclo (Ile-Thr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclomethionylvaline (Cyclo (Met-Val)), cycloarginylisoleucine (Cyclo (Arg-Ile)], cycloglutamyl leucine [Cyclo (Glu-Leu)], and cyclothreonyl
  • cyclic dipeptide salt refers to any pharmacologically acceptable salt (including inorganic salts and organic salts) of the cyclic dipeptide, such as sodium salt and potassium salt of the cyclic dipeptide. , Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate , Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, and the like), but are not limited thereto. Cyclic dipeptide salts can be readily prepared by those skilled in the art by any method known in the art.
  • the cyclic dipeptide used in the present invention can be prepared according to a method known in the art. For example, it may be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or may be synthesized by dehydration and cyclization of a linear peptide. JP 2003-252896 A, Journal of Peptide ⁇ Science, 10, 737-737, 2004.
  • an animal and plant derived peptide heat-treated product rich in cyclic dipeptide can be obtained by further heat-treating an animal and plant derived peptide obtained by subjecting a raw material containing animal and plant derived protein to enzyme treatment or heat treatment. From these points, the cyclic dipeptide or salt thereof used in the present invention may be chemically or biologically synthesized, or may be obtained from an animal or plant derived peptide.
  • Animal and Plant Derived Peptide in the present specification is not particularly limited.
  • soybean peptide, tea peptide, malt peptide, milk peptide, placenta peptide, collagen peptide and the like can be used.
  • Animal and plant-derived peptides may be prepared and used from animal or plant-derived proteins or raw materials containing proteins, but commercially available products may also be used.
  • Soybean peptide refers to a low molecular weight peptide obtained by subjecting soy protein to enzyme treatment or heat treatment to lower the molecular weight of the protein. Soybeans (scientific name: Glycine max) used as a raw material can be used without restriction of varieties and production areas, and can also be used in processed products such as pulverized products.
  • tea peptide refers to a low molecular weight peptide derived from tea obtained by subjecting a tea (including tea leaves or tea husk) extract to enzyme treatment or heat treatment to lower the protein.
  • a tea leaf used as an extraction raw material, a tea leaf (scientific name: Camellia sinensis) manufactured tea leaf leaf, stem, etc. that can be extracted and used can be used.
  • the form is not limited to large leaves or powders. The harvest time of tea leaves can also be selected appropriately according to the desired flavor.
  • malt peptide refers to a malt-derived low molecular weight peptide obtained by subjecting an extract obtained from malt or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of the protein.
  • malt peptide used as a raw material can be used without restriction of varieties and production areas, barley malt obtained by germinating barley seeds is particularly preferably used. In the present specification, barley malt may be simply referred to as malt.
  • milk peptide is a product obtained by decomposing milk protein, which is a component derived from natural milk, into a molecule in which at least several amino acids are bound. More specifically, it is obtained by hydrolyzing milk protein such as whey (whey protein) or casein with an enzyme such as proteinase, and filtering and sterilizing and / or concentrating and drying the filtrate. Examples include whey peptides and casein peptides.
  • placenta peptide placenta is the placenta of mammals and has been used as a health food, cosmetics, and pharmaceutical material in recent years because of its excellent functionality.
  • placenta peptide refers to a placenta that has been solubilized and reduced in molecular weight by enzyme treatment or subcritical treatment.
  • extracts obtained from plant placenta are used in health foods, cosmetics, etc. as having a physiological effect equivalent to placenta derived from placenta. be called.
  • the “placenta peptide” in the present specification includes those obtained by subjecting plant placenta to enzyme treatment or subcritical treatment, solubilization and low molecular weight.
  • Collagen peptide refers to a low molecular peptide obtained by subjecting collagen or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of collagen.
  • Collagen is a major protein in animal connective tissue and is the most abundant protein in mammalian bodies including humans.
  • high temperature heat treatment means that the treatment is performed for a certain period of time at a temperature of 100 ° C. or higher and a pressure exceeding atmospheric pressure.
  • a pressure-resistant extraction device, a pressure cooker, an autoclave, or the like can be used according to conditions.
  • the temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, but is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, and still more preferably 120 ° C to 140 ° C.
  • this temperature shows the value which measured the exit temperature of the extraction column, when using a pressure-resistant extraction apparatus as a heating apparatus, and when using an autoclave as a heating apparatus, it is the temperature of the center temperature in a pressure vessel. The measured value is shown.
  • the pressure in the high-temperature heat treatment is not particularly limited as long as it is a pressure exceeding atmospheric pressure, but is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, and even more preferably 0.101 MPa to 0. 48 MPa.
  • the high-temperature heat treatment time is not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably about 60 minutes to 300 minutes. It is.
  • the high-temperature heat treatment conditions for the animal and plant derived peptides are not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but preferably [temperature: pressure: time] is [100 ° C. to 170 ° C .: 0.101 MPa to 0.001. 79 MPa: 15 minutes to 600 minutes], more preferably [110 ° C. to 150 ° C .: 0.101 MPa to 0.60 MPa: 30 minutes to 500 minutes], even more preferably [120 ° C. to 140 ° C .: 0.101 MPa to 0 48 MPa: 60 minutes to 300 minutes].
  • the specific cyclic dipeptide in the heat-treated product of animal and plant derived peptides does not satisfy the desired content, the specific cyclic dipeptide that is deficient may be appropriately added using other animal or plant derived peptides, commercial products, or synthetic products. it can.
  • composition for inhibiting carnosine dipeptidase 1 5-1 Composition for inhibiting carnosine dipeptidase 1 containing cyclic dipeptide
  • One embodiment of the present invention is a composition for inhibiting carnosine dipeptidase 1 comprising a specific cyclic dipeptide or a salt thereof as an active ingredient.
  • composition for inhibiting carnosine dipeptidase 1 of the present invention comprises cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamate [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys).
  • the number of cyclic dipeptides or salts thereof contained in the composition for inhibiting carnosine dipeptidase 1 of the present invention is not particularly limited, but the present invention may include three or more selected from the above-mentioned cyclic dipeptides or salts thereof. preferable.
  • cyclotryptophanyl tyrosine [Cyclo (Trp-Tyr)], cycloisoleucillysine [Cyclo (Ile-Lys)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)] ), Cycloisoleucine threonine [Cyclo (Ile-Thr)], cyclomethionylserine [Cyclo (Met-Ser)], cyclomethionylvaline [Cyclo (Met-Val)], cycloarginylisoleucine [Cyclo (Arg) -Ile)], cycloglutamyl leucine [Cyclo (Glu-Leu)], and cyclothreonylglutamic acid [Cyclo (Thr-Glu)], preferably one or two or more, cyclotryptophanyl Tyrosine (Cyclo (Trp-Tyr)], cycloisoleucillysine [Cy
  • the content of the cyclic dipeptide or the salt thereof in the composition for inhibiting carnosine dipeptidase 1 of the present invention may be an amount that can achieve the desired effect of the present invention in consideration of its administration form, administration method, etc. It is not particularly limited.
  • cyclolysyl lysine [Cyclo (Lys-Lys)] in the composition for inhibiting carnosine dipeptidase 1 of the present invention Cycloisoleucylglutamic acid (Cyclo (Ile-Glu)), cycloisoleucillysine (Cyclo (Ile-Lys)), cycloleucyltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met- Val)), cycloisoleuyl threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloarginyl isoleucine (Cyclo (Arg-Ile)), cyclotrypto
  • ppm / Brix 200 ⁇ g / 100 g / Bx or more, preferably 10 ppm / Brix or more, more preferably 20 ppm / Brix or more, 8000 ppm / Brix or less, preferably 800 ppm / Brix or less, more preferably 80 ppm / Brix or less.
  • the above content can also be applied when a synthetic or purified cyclic dipeptide or a salt thereof is used.
  • content of cyclic dipeptide or its salt is represented by the quantity per Brix (Brix: Bx) as above-mentioned.
  • amount per Brix means an amount determined by a value corresponding to a mass percentage of a sucrose solution at 20 ° C. (an aqueous solution containing only sucrose as a solute).
  • ppm used in the present specification means ppm of weight / volume (w / v), and 1.0 ppm / Brix is 0.1 mg / wt when the specific gravity of the solvent is 1. Converted to mL and converted to 0.01% by weight.
  • the content of the cyclic dipeptide or a salt thereof can be measured according to a known method. For example, it can be measured using LC-MS / MS or a saccharimeter.
  • carnosine dipeptidase 1 maintains the body concentration of carnosine degraded by carnosine dipeptidase 1 in mammals such as humans, or suppresses a decrease in the concentration.
  • Carnosine functions include proton buffering activity, calcium secretion and calcium sensitivity control, antioxidant action, metal ion chelate action, extracellular donor of histidine / histamine, hyperglycemia improvement action, anti-inflammatory action, generation of advanced glycation end products Examples thereof include suppression, suppression of cell death due to cerebral ischemia, accumulation of amyloid ⁇ , immunoregulation in Alzheimer's disease (AD) model mice, and the like.
  • composition for inhibiting carnosine dipeptidase 1 of the present invention can contain any additive and any commonly used component in addition to the cyclic dipeptide or a salt thereof, depending on its form.
  • additives and / or ingredients include vitamins such as vitamin E and vitamin C, bioactive ingredients such as minerals, nutritional ingredients, and fragrances, as well as excipients and binders incorporated in the formulation.
  • Emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, colorants, coagulants, or coating agents but are not limited thereto. It is not something.
  • composition for inhibiting carnosine dipeptidase 1 of the present invention is characterized by containing the aforementioned cyclic dipeptide or a salt thereof as an active ingredient, and the cyclic dipeptide or a salt thereof inhibits the activity of carnosine dipeptidase 1.
  • the in vivo concentration of carnosine decomposed by carnosine dipeptidase 1 is maintained, or a decrease in the concentration is suppressed.
  • Carnosine is maintained at a high concentration in the body, thereby reducing cognitive function, diabetes, immune function, vascular or tissue inflammation, oxidative stress, or production of advanced glycation end products, Alzheimer's disease, or autism Prevention or improvement can be carried out effectively.
  • the composition of the present invention is used for the prevention or improvement of various diseases, Alzheimer's, or autism resulting from the production of cognitive function decline, diabetes, immune function decline, vascular or tissue inflammation, oxidative stress or advanced glycation end products.
  • This is a composition for inhibiting carnosine dipeptidase 1.
  • the composition for inhibiting carnosine dipeptidase 1 of the present invention is used for various diseases caused by cognitive decline, diabetes, immune function decline, vascular or tissue inflammation, oxidative stress or production of advanced glycation end products, Alzheimer's Or a composition for preventing or ameliorating autism.
  • “prevention or improvement” includes both concepts of making the current state a better state and preventing the current state from becoming worse than the current state. Terms such as treatment, recovery, alleviation, alleviation can also be included.
  • composition for inhibiting carnosine dipeptidase 1 of the present invention is prepared by a known method in the form of a solid agent such as a tablet (including a coated tablet), a granule, a powder, a powder, or a capsule, a normal solution, a suspension, Alternatively, it can be formulated into a liquid such as an emulsion. These compositions can be taken with water or the like as it is. Moreover, after preparing the form (for example, powder form and granule form) which can be mix
  • composition for inhibiting carnosine dipeptidase 1 of the present invention can be provided in the form of an agent as an example, but is not limited to this form.
  • the agent can be provided as a composition as it is or as a composition containing the agent.
  • the composition of the present invention include, but are not limited to, a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like.
  • Non-limiting examples of food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
  • composition for inhibiting carnosine dipeptidase 1 of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it does not belong to pharmaceuticals, quasi drugs, cosmetics, etc. or the Pharmaceutical Affairs Law, but cognitive function decline, diabetes, immune function decline, inflammation of blood vessels or tissues, oxidative stress or production of advanced glycation end products Use as a composition that explicitly or implicitly promotes various diseases, Alzheimer's, or the prevention or amelioration effect of autism.
  • the present invention relates to the composition for inhibiting carnosine dipeptidase 1, which is labeled with the function exhibited by carnosine dipeptidase 1 inhibition.
  • a display or functional display is not particularly limited, but for example, “suppress cognitive function decrease”, “expect cognitive function maintenance”, “suppress blood glucose level increase”, “immune function ”Enhance”, “antioxidant”, “reduce oxidative stress”, “anti-glycation”, “reduce glycation stress”, “suppress vascular inflammation”, “alzheimer's disease” Examples such as “expect prevention or improvement”, “expect prevention or improvement of autism”, etc., or display or functional indication that can be equated with these.
  • indications such as the indication and the functionality indication may be attached to the composition itself, or may be attached to a container or packaging of the composition.
  • the composition for inhibiting carnosine dipeptidase 1 of the present invention can be ingested by an appropriate method according to the form.
  • the intake method is not particularly limited as long as the cyclic dipeptide or a salt thereof according to the present invention can be transferred into the circulating blood.
  • oral solid preparations, oral liquid preparations such as internal liquids or syrups, or parenteral preparations such as injections, external preparations, suppositories or transdermal absorption agents can be used. It is not limited to.
  • “ingestion” is used to include all aspects such as ingestion, taking, or drinking.
  • the application amount of the composition for inhibiting carnosine dipeptidase 1 of the present invention is appropriately set depending on the form, administration method, purpose of use, and age, weight and symptom of the patient or animal to be administered, and is not constant.
  • the effective human intake of the composition of the present invention is not constant, for example, the weight of the cyclic dipeptide or salt thereof as the active ingredient is preferably 10 mg or more, more preferably 100 mg per day for a human body weight of 50 kg. That's it.
  • administration may be performed once or several times within one day within a desired dose range.
  • the administration period is also arbitrary.
  • the effective human intake of the composition of the present invention refers to the intake of the composition for inhibiting carnosine dipeptidase 1 of the present invention that exhibits an effective effect in humans, and the cyclic dipeptide contained in the composition
  • the type is not particularly limited.
  • the subject of application of the composition for inhibiting carnosine dipeptidase 1 of the present invention is preferably human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or mice, rats and guinea pigs. Or a laboratory animal such as a monkey.
  • the amount used per day for about 20 g per mouse is the content of the active ingredient in the composition, the state of the subject, weight, sex, age, etc.
  • the total amount of the cyclic dipeptide or its salt is preferably 10 mg / kg or more, more preferably 100 mg / kg or more.
  • the carnosine dipeptidase 1 inhibitory action of the cyclic dipeptide or a salt thereof delays the degradation of carnosine from carnosine dipeptidase 1, and targets tissues and organs. Can effectively deliver the carnosine.
  • the carnosine concentration in the body can be maintained higher by combining carnosine with a composition for inhibiting carnosine dipeptidase 1 so that the action of carnosine is effectively improved. Can be enhanced.
  • the combined composition of the present invention can be a composition for inhibiting carnosine dipeptidase 1 because it contains the above-mentioned specific cyclic dipeptide or a salt thereof.
  • the combination composition of the present invention is preferably used for the uses described in 5-4 above from the viewpoint of enhancing the carnosine effect. That is, the combination composition of the present invention is preferably used for various diseases, Alzheimer's disease, or autism caused by cognitive decline, diabetes, immune function decline, blood vessel or tissue inflammation, oxidative stress or production of advanced glycation end products. It is a composition for prevention or improvement.
  • the combination composition of the present invention can be a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like, but is not limited thereto.
  • food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
  • Carnosine in the present invention is a dipeptide composed of ⁇ -alanine and histidine and is also referred to as ⁇ -alanyl histidine.
  • Carnosine includes all of D-form (D-carnosine), L-form (L-carnosine), and DL-form (DL-carnosine).
  • L-form (L-carnosine) and DL-form preferably L-form (L-carnosine) and DL-form.
  • the CAS registration number of D-form (D-carnosine) is 5853-00-9, and the CAS registration number of L-form (L-carnosine) is 305-84-0.
  • the method of obtaining carnosine used in the present invention is not particularly limited, and may be any natural one derived from animals or one obtained by chemical synthesis. In the present invention, commercially available carnosine is preferably used. In addition, the content of carnosine in the combination composition of the present invention is not particularly limited as long as the desired effect of the present invention is obtained in consideration of the administration form, administration method, and the like. .
  • the amount ratio of the above-mentioned cyclic dipeptide or a salt thereof and carnosine in the combination composition of the present invention is not particularly limited as long as the desired effect of the present invention is obtained.
  • the ratio (cyclic dipeptide or a salt thereof: carnosine) in the combination composition of the present invention is, for example, 1: 1000 to 1: 1, preferably 1: 950 to 1: 5, more preferably 1: 900 to 1:10.
  • a cyclic dipeptide or a salt thereof for inhibiting carnosine dipeptidase 1
  • One aspect of the present invention is the use of a specific cyclic dipeptide or a salt thereof having amino acid as a constituent unit for inhibiting carnosine dipeptidase 1.
  • cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucyl glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucyl tyrosine [Cyclo ( Leu-Tyr)], cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloarginyl isoleucine [ Cyclo (Arg-Ile)], cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyl tryptophan (Cyclo (Phe-Trp)), cycloasparaginyl leucine
  • non-therapeutic is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.
  • One embodiment of the present invention is a method for inhibiting carnosine dipeptidase 1 using a specific cyclic dipeptide having amino acid as a constituent unit or a salt thereof as an active ingredient.
  • the method is preferably cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], Tyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cyclo Arginylisoleucine [Cyclo (Arg-Ile)], cyclotryptophanyltyrosine [Cyclo (Trp-Tyr)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)], cycloasparaginylleucine [Cyclo (Asn- Le
  • Another aspect relating to the method comprises a method of inhibiting carnosine dipeptidase 1, comprising administering to a subject in need of inhibition of carnosine dipeptidase 1 a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient. It is.
  • cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucyl glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucyl tyrosine [Cyclo ( Leu-Tyr)], cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloarginyl isoleucine [ Cyclo (Arg-Ile)], cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyl tryptophan (Cyclo (Phe-Trp)), cycloasparaginyl leucine
  • the subject requiring inhibition of carnosine dipeptidase 1 is the same as the subject of application of the composition for inhibiting carnosine dipeptidase 1 of the present invention.
  • the therapeutically effective amount refers to the carnosine degradation of carnosine dipeptidase 1 when the composition for inhibiting carnosine dipeptidase 1 of the present invention is administered to the above-mentioned subject as compared to a subject not administered.
  • the specific effective amount is appropriately set according to the administration form, administration method, purpose of use and age, weight, symptom, etc. of the subject and is not constant.
  • the specific cyclic dipeptide or a salt thereof may be administered as it is or as a composition containing the specific cyclic dipeptide or a salt thereof so that the therapeutically effective amount is obtained.
  • Example 1 Examination of the inhibitory effect of serum carnosinase (CNDP1) activity by cyclic dipeptides Various cyclic dipeptide preparations were chemically synthesized and used for the test. Recombinant Human Carnosine Dipeptidase 1 / CNDP1 (R & D systems) was used as human serum carnosinase CNDP1. Carnosine manufactured by Tokyo Chemical Industry Co., Ltd. was used. The serum carnosinase (CNDP1) activity inhibitory effect was examined at room temperature by the following procedure.
  • the correction value was calculated by subtracting the fluorescence intensity in the sample to which the buffer was added instead of the enzyme (CNDP1), and the fluorescence value in each cyclic dipeptide-containing sample when the correction value of the fluorescence intensity in the control was taken as 100%.
  • the intensity correction value was defined as CNDP1 residual activity (%). The results are shown in Table 1.
  • Example 2 Examination of Serum Carnosinase (CNDP1) Activity Inhibitory Effect by Linear Dipeptide
  • CNDP1 tissue carnosinase
  • Various linear dipeptide preparations purchased from BACHEM were used for the test. The other materials were the same as in Example 1, and the inhibitory action of serum carnosinase (CNDP1) activity by the linear dipeptide was examined in the same manner as in Example 1. The results are shown in Table 2.
  • the linear dipeptide known for CNDP2 inhibitory activity did not show an inhibitory effect on serum carnosinase (CNDP1) activity even when the concentration was 500 ⁇ M. From these results, it was revealed that linear dipeptides known to have CNDP2 inhibitory activity have no inhibitory action on serum carnosinase (CNDP1) activity. Moreover, from the above results, the cyclic dipeptide shown in Table 1 inhibits the activity of serum carnosinase (CNDP1) based on a structure different from that of the linear dipeptide known to have CNDP2 inhibitory activity. It was suggested that the inhibitor and the inhibitor of tissue carnosinase (CNDP2) are different from each other and have no relation.
  • the present invention provides a composition for inhibiting carnosine dipeptidase 1 containing a specific cyclic dipeptide or a salt thereof as an active ingredient. Since the present invention provides a new means that contributes to prevention or improvement of cognitive function decline or the like, the industrial applicability is high.

Abstract

Provided are a carnosine dipeptidase 1 inhibitor composition, a use for said composition in order to inhibit carnosine dipeptidase 1, and a method for inhibiting carnosine dipeptidase 1. The present invention demonstrates the discovery of a specific ring-shaped dipeptide or salt thereof exhibiting an inhibitory activity against carnosine dipeptidase 1, and thus, provides a novel and effective means that contributes to the prevention or amelioration of a cognitive function decline or the like.

Description

環状ジペプチド含有血清カルノシン分解酵素阻害用組成物Composition for inhibiting serum carnosine degrading enzyme containing cyclic dipeptide
　本発明は、血清カルノシン分解酵素阻害用組成物に関する。さらに詳しくは、本発明は、特定の環状ジペプチド又はその塩を有効成分として含むカルノシンジペプチダーゼ１阻害用組成物、カルノシンジペプチダーゼ１を阻害するための特定の環状ジペプチド又はその塩の使用、カルノシンジペプチダーゼ１を阻害する方法、及び特定の環状ジペプチド又はその塩とカルノシンとを含む組成物に関する。 The present invention relates to a composition for inhibiting serum carnosine degrading enzyme. More specifically, the present invention relates to a composition for inhibiting carnosine dipeptidase 1 containing a specific cyclic dipeptide or a salt thereof as an active ingredient, the use of a specific cyclic dipeptide or a salt thereof for inhibiting carnosine dipeptidase 1, carnosine The present invention relates to a method for inhibiting peptidase 1 and a composition comprising a specific cyclic dipeptide or a salt thereof and carnosine.
　カルノシンは、β－アラニンとヒスチジンとからなるジペプチドであり、ヒト等の哺乳動物では筋肉や神経組織に高濃度に存在している。カルノシンの作用としては、（１）プロトンバッファーリング活性、（２）カルシウム分泌とカルシウム感受性制御、（３）抗酸化作用、（４）金属イオンキレート作用、（５）ヒスチジン／ヒスタミンの細胞外供与体、（６）高血糖改善作用、（７）抗炎症作用等が知られている。また、カルノシンの作用については、終末糖化産物の生成抑制や、脳虚血による細胞死の抑制、アルツハイマー病（ＡＤ）モデルマウスにおけるアミロイドβの蓄積作用、免疫調節作用等も報告されている。このようにカルノシンは体内における様々な機能に寄与しているが、カルノシン分解酵素によって分解されることがその薬理学的作用の発揮にとって課題となっている。 Carnosine is a dipeptide composed of β-alanine and histidine, and is present in high concentrations in muscle and nerve tissues in mammals such as humans. Carnosine's actions include (1) proton buffering activity, (2) calcium secretion and calcium sensitivity control, (3) antioxidant action, (4) metal ion chelate action, (5) histidine / histamine extracellular donor (6) Hyperglycemia improving action, (7) Anti-inflammatory action, etc. are known. As for the action of carnosine, the production of glycated end products, the suppression of cell death due to cerebral ischemia, the accumulation of amyloid β in Alzheimer's disease (AD) model mice, the immunoregulatory action, and the like have been reported. As described above, carnosine contributes to various functions in the body. However, degradation by carnosine degrading enzyme is a problem for exerting its pharmacological action.
　カルノシン分解酵素には血清カルノシナーゼ（carnosine dipeptidase 1；ＣＮＤＰ１）と組織カルノシナーゼ（carnosine dipeptidase 2；ＣＮＤＰ２）との２種類が存在することが知られている。このうちＣＮＤＰ１は、高等霊長類（ヒト及び大型のサル）にのみ存在し、ほとんどの他の哺乳動物には存在しないことが示されている（非特許文献１）。これらＣＮＤＰ１及びＣＮＤＰ２は互いに相同性の高いタンパク質ではあるが、組織分布や酵素的特性は異なっており、両者はそれぞれ異なる機能を有するものと考えられている。 It is known that there are two types of carnosine-degrading enzymes: carnosine dipeptidase 1; CNDP1 and tissue carnosinase 2 (CNDP2). Among these, CNDP1 has been shown to exist only in higher primates (human and large monkeys) and not in most other mammals (Non-patent Document 1). Although these CNDP1 and CNDP2 are highly homologous proteins, their tissue distribution and enzymatic characteristics are different, and both are considered to have different functions.
　ＣＮＤＰ２に関しては、例えば、ベスタチンがその阻害剤として知られており（非特許文献２）、その他にはβ－アラニン、並びにGly-L-His及びL-Pro-L-Hisのような直鎖状ジペプチドがＣＮＤＰ２の阻害に有効であることが報告されている（特許文献１）。一方、ＣＮＤＰ１については、例えばフェナントロリンがその阻害剤として報告されているが（非特許文献３）、ＣＮＤＰ１の活性阻害に着目したカルノシン分解抑制剤はあまり知られていないのが現状である。 Regarding CNDP2, for example, bestatin is known as an inhibitor (Non-patent Document 2), and others are β-alanine and linear chains such as Gly-L-His and L-Pro-L-His. It has been reported that dipeptides are effective in inhibiting CNDP2 (Patent Document 1). On the other hand, with regard to CNDP1, for example, phenanthroline has been reported as an inhibitor (Non-patent Document 3), but there are few known carnosine degradation inhibitors that focus on inhibition of CNDP1 activity.
　上述した通りＣＮＤＰ１及びＣＮＤＰ２は互いに異なるタンパク質であることから、それぞれの酵素に対する阻害剤も互いに異なるものと考えられている。実際、上記のＣＮＤＰ２阻害剤であるベスタチンはＣＮＤＰ１の阻害には効果を持たないことが明記されている（非特許文献４）。また、上記に示したフェナントロリンは、ＣＮＤＰ１の阻害活性を有するものの、その副作用として経口毒性を示すことが知られている。そのため、より安全なＣＮＤＰ１の阻害剤を見出すことができれば、ＣＮＤＰ１の活性に関連する疾患や症状への臨床適用も可能になるものと考えられている。 As described above, since CNDP1 and CNDP2 are different proteins, the inhibitors for the respective enzymes are also considered to be different from each other. In fact, it is specified that bestatin, which is the above CNDP2 inhibitor, has no effect on the inhibition of CNDP1 (Non-patent Document 4). Moreover, although the phenanthroline shown above has CNDP1 inhibitory activity, it is known to show oral toxicity as a side effect thereof. Therefore, if a safer inhibitor of CNDP1 can be found, clinical application to diseases and symptoms related to the activity of CNDP1 is considered possible.
　ＣＮＤＰ１に関しては、非特許文献５において、ｄｂ／ｄｂマウスにヒト血清カルノシナーゼ（ＣＮＤＰ１）を遺伝子導入した動物モデルにおいて、若年期より空腹時血糖値とＨｂＡ１ｃが高値を示し、体重減少を示すなどの糖尿病様症状が現れることを認めている。即ち、血清カルノシナーゼ（ＣＮＤＰ１）によるカルノシン分解亢進が、疾患発症原因になる可能性が示唆されている。従って、血清カルノシン分解酵素（ＣＮＤＰ１）阻害用組成物は、Ｌ－カルノシンを血漿、標的器官あるいはその他の器官に効率的に送達させ、糖尿病や酸化ストレス、終末糖化産物の産生に起因する各種疾患に対して予防効果を高めるためのアプローチとして考えられている。 Regarding CNDP1, in non-patent document 5, in an animal model in which human serum carnosinase (CNDP1) is introduced into a db / db mouse, diabetes, such as fasting blood glucose level and HbA1c are higher than in younger age, indicating weight loss, etc. Admits that symptoms appear. That is, it has been suggested that enhanced carnosine degradation by serum carnosinase (CNDP1) may cause disease onset. Therefore, a composition for inhibiting serum carnosine degrading enzyme (CNDP1) efficiently delivers L-carnosine to plasma, target organs or other organs, and is effective for various diseases caused by diabetes, oxidative stress, and production of advanced glycation end products. It is considered as an approach to increase the preventive effect.
　また、非特許文献６等の複数の文献において、血清カルノシナーゼ（ＣＮＤＰ１）遺伝子における特定の遺伝子多型（（ＣＴＧ）ｎ）と糖尿病性腎障害の発症との間に相関が認められていることが報告されている。これに関連して、非特許文献７においてはホモ接合型（ＣＴＧ）５保持者において糖尿病性腎障害の発症リスクが低く、血清カルノシナーゼ活性が低いという報告が存在している。従って、血清カルノシナーゼ活性を抑制することがカルノシン濃度の維持に重要であり、関連する疾患の予防や治療に有効である可能性があると考えられている。 Further, in a plurality of documents such as Non-Patent Document 6, there is a correlation between a specific gene polymorphism ((CTG) n) in the serum carnosinase (CNDP1) gene and the onset of diabetic nephropathy. It has been reported. In this connection, Non-Patent Document 7 reports that homozygous (CTG) 5 carriers have a low risk of developing diabetic nephropathy and low serum carnosinase activity. Therefore, suppressing serum carnosinase activity is important for maintaining carnosine concentration, and is considered to be effective in preventing or treating related diseases.
　また、ヒトにおけるカルノシン経口摂取後の体内動態試験の検証例としては、非特許文献８が挙げられる。当該文献によれば、カルノシン６０ｍｇ／ｋｇ摂取後各時間におけるカルノシン血中濃度の個人差は大きく、摂取前と比較して血中カルノシン濃度に著しい上昇が認められない被験者も存在し（２５名中１７名）、上昇が認められた群ではそうではない群と比較して血清カルノシナーゼの活性やタンパク質量が有意に低かった。このことから血清カルノシナーゼ（ＣＮＤＰ１）の働きを抑制することが血中カルノシン濃度維持に有効である可能性が高いと考えられている。 In addition, Non-Patent Document 8 can be cited as a verification example of a pharmacokinetic test after oral ingestion of carnosine in humans. According to this document, individual differences in the blood concentration of carnosine at each time after ingestion of carnosine 60 mg / kg are large, and there are some subjects in which no significant increase in blood carnosine concentration was observed compared to before intake (among 25 subjects). 17), the activity of serum carnosinase and the amount of protein were significantly lower in the group in which the increase was observed than in the group in which the increase was not. From this, it is considered that there is a high possibility that suppressing the action of serum carnosinase (CNDP1) is effective in maintaining the blood carnosine concentration.
　このようにＣＮＤＰ１は、哺乳動物として特にヒトの体内において様々な影響を及ぼしていることから、この活性を効果的に阻害するための安全性の高い薬剤が強く求められている。 Thus, since CNDP1 exerts various influences in the human body as a mammal, there is a strong demand for highly safe drugs for effectively inhibiting this activity.
国際公開ＷＯ２００４／０６４８６６号International Publication WO 2004/064866
　本発明の課題は、生物安全性が高く、カルノシンの血中濃度の維持に寄与する血清カルノシン分解酵素（ＣＮＤＰ１）阻害用組成物を提供することにある。また、本発明の課題は、ＣＮＤＰ１を阻害するための当該組成物の使用、ＣＮＤＰ１を阻害する方法、及び生物安全性が高く、カルノシンの血中濃度の維持に寄与する組成物等を提供することにある。 An object of the present invention is to provide a composition for inhibiting serum carnosine degrading enzyme (CNDP1) that has high biosafety and contributes to maintaining the blood concentration of carnosine. Another object of the present invention is to provide a use of the composition for inhibiting CNDP1, a method for inhibiting CNDP1, and a composition that contributes to maintaining the blood concentration of carnosine with high biosafety. It is in.
　本発明者らは、上記課題について鋭意検討した結果、環状ジペプチドの利用に着目した。環状ジペプチドは、直鎖状ジペプチドの末端に存在するアミノ基とカルボキシル基とが脱水縮合することにより生成した環状構造を有するジペプチドであり、近年ではその様々な生理活性が注目を受けている。本発明者らは、天然アミノ酸の組合せからなる約２００種類にも及ぶ多数の環状ジペプチドについて鋭意検討し、その中から特定の環状ジペプチドがＣＮＤＰ１の阻害活性を有することを初めて見出した。かかる知見に基づき、本発明者らは本発明を完成するに至った。 As a result of intensive studies on the above problems, the present inventors have focused on the use of cyclic dipeptides. A cyclic dipeptide is a dipeptide having a cyclic structure formed by dehydration condensation of an amino group and a carboxyl group present at the end of a linear dipeptide. In recent years, various physiological activities have received attention. The present inventors have intensively studied about a large number of about 200 kinds of cyclic dipeptides composed of combinations of natural amino acids, and found for the first time that a specific cyclic dipeptide has CNDP1 inhibitory activity. Based on this finding, the present inventors have completed the present invention.
　即ち、本発明は以下に関するが、これらに限定されない。
（１）アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として含有するカルノシンジペプチダーゼ１阻害用組成物であって、
　前記環状ジペプチド又はその塩が、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記カルノシンジペプチダーゼ１阻害用組成物。
（２）認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善用である、（１）に記載のカルノシンジペプチダーゼ１阻害用組成物。
（３）環状ジペプチド又はその塩が、動植物由来ペプチドから得られるものである、（１）又は（２）に記載のカルノシンジペプチダーゼ１阻害用組成物。
（４）環状ジペプチド又はその塩の含有量が２００μｇ／１００ｇ／Ｂｘ以上である、（１）～（３）のいずれかに記載のカルノシンジペプチダーゼ１阻害用組成物。
（５）環状ジペプチド又はその塩の含有量が１０００μｇ／１００ｇ／Ｂｘ以上である、（１）～（３）のいずれかに記載のカルノシンジペプチダーゼ１阻害用組成物。
（６）カルノシンジペプチダーゼ１阻害により発揮される機能の表示を付した、（１）～（５）のいずれかに記載のカルノシンジペプチダーゼ１阻害用組成物。
（７）機能の表示が、「認知機能の低下を抑制する」、「認知機能の維持を期待する」、「血糖値の上昇を抑制する」、「免疫機能を高める」、「抗酸化作用を期待する」、「酸化ストレスを低減する」、「抗糖化作用を期待する」、「糖化ストレスを低減する」、「血管の炎症を抑制する」、「アルツハイマー症の予防若しくは改善を期待する」、及び「自閉症の予防若しくは改善を期待する」からなる群から選択されるものである、（６）に記載の組成物。
（８）前記組成物が剤である、（１）～（７）のいずれかに記載のカルノシンジペプチダーゼ１阻害用組成物。
（９）カルノシンジペプチダーゼ１を阻害するための、アミノ酸を構成単位とする環状ジペプチド又はその塩の使用であって、
　前記環状ジペプチド又はその塩が、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記使用。
（１０）アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として使用する、カルノシンジペプチダーゼ１を阻害する方法であって、
　前記環状ジペプチド又はその塩が、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記方法。 That is, the present invention relates to the following, but is not limited thereto.
(1) A composition for inhibiting carnosine dipeptidase 1 comprising, as an active ingredient, a cyclic dipeptide having an amino acid as a structural unit or a salt thereof,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine. Siltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucine threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloarginylisoleucine (Cyclo (Arg-Ile)), cyclotryptophanyltyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cycloasparaginylleucine (Cyclo (Asn -Leu)], cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)], Cyclovalyllici Including one or more selected from the group consisting of [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] The above-mentioned composition for inhibiting carnosine dipeptidase 1
(2) For prevention or improvement of various diseases, Alzheimer's, or autism caused by cognitive function decline, diabetes, immune function decline, vascular or tissue inflammation, oxidative stress or advanced glycation end products, (1) The composition for carnosine dipeptidase 1 inhibition as described in 1 above.
(3) The composition for carnosine dipeptidase 1 inhibition according to (1) or (2), wherein the cyclic dipeptide or a salt thereof is obtained from an animal or plant-derived peptide.
(4) The composition for inhibiting carnosine dipeptidase 1 according to any one of (1) to (3), wherein the content of the cyclic dipeptide or a salt thereof is 200 μg / 100 g / Bx or more.
(5) The composition for inhibiting carnosine dipeptidase 1 according to any one of (1) to (3), wherein the content of the cyclic dipeptide or a salt thereof is 1000 μg / 100 g / Bx or more.
(6) The composition for inhibiting carnosine dipeptidase 1 according to any one of (1) to (5), which is labeled with a function exhibited by carnosine dipeptidase 1 inhibition.
(7) The function display is “suppresses cognitive function decline”, “expects maintenance of cognitive function”, “suppresses increase in blood glucose level”, “improves immune function”, “antioxidant action” `` Expect '', `` Reduce oxidative stress '', `` Expect anti-glycation effect '', `` Reduce glycation stress '', `` Inhibit vascular inflammation '', `` Expect prevention or improvement of Alzheimer's disease '', And the composition according to (6), which is selected from the group consisting of “expecting prevention or improvement of autism”.
(8) The composition for inhibiting carnosine dipeptidase 1 according to any one of (1) to (7), wherein the composition is an agent.
(9) Use of a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for inhibiting carnosine dipeptidase 1,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine. Siltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucine threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloarginylisoleucine (Cyclo (Arg-Ile)), cyclotryptophanyltyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cycloasparaginylleucine (Cyclo (Asn -Leu)], cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)], Cyclovalyllici Including one or more selected from the group consisting of [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] The use as described above.
(10) A method for inhibiting carnosine dipeptidase 1, using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine. Siltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucine threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloarginylisoleucine (Cyclo (Arg-Ile)), cyclotryptophanyltyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cycloasparaginylleucine (Cyclo (Asn -Leu)], cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)], Cyclovalyllici Including one or more selected from the group consisting of [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] The method as described above.
　本発明によって、優れた血清カルノシン分解酵素（ＣＮＤＰ１）阻害効果を有する組成物を提供することができる。本発明の組成物を利用すれば、ＣＮＤＰ１の機能抑制に伴うカルノシンの分解遅延効果が得られるため、より高濃度のカルノシンを血漿、標的器官あるいはその他の器官に効率的に送達させることが可能となる。そのため、本発明の組成物は、元来カルノシンに関して知られている各種薬理学的作用（統合失調症などに伴う認知機能低下、糖尿病、免疫機能低下、血管や組織の炎症、酸化ストレスに起因する各種疾患発症、アルツハイマー、自閉症に対する予防、改善効果）の向上に有効であり得る。 According to the present invention, a composition having an excellent inhibitory effect on serum carnosine degrading enzyme (CNDP1) can be provided. By using the composition of the present invention, the effect of delaying degradation of carnosine accompanying the suppression of CNDP1 function can be obtained, so that a higher concentration of carnosine can be efficiently delivered to plasma, target organ or other organs. Become. Therefore, the composition of the present invention originates from various pharmacological actions that are originally known for carnosine (cognitive decline associated with schizophrenia, diabetes, immune function decline, inflammation of blood vessels and tissues, oxidative stress, etc. It can be effective in improving various diseases onset, prevention of Alzheimer's disease, and autism.
　本発明の組成物に有効成分として含まれる環状ジペプチド又はその塩は、食品タンパク質由来ペプチドの熱処理物にも含まれていることから安全性は高く、副作用は従来の医薬品に比して極めて少ないと考えられる。また、環状ジペプチドは直鎖状ジペプチドと比較して親油性に優れており、油性基材への高濃度充填も十分に可能である。そのため、本発明の組成物は、製剤化における使用性に優れているといえる。さらに、環状ジペプチドは脂溶性に富み、且つ単なるペプチド結合のみで構成されるジペプチドではないため、消化管に分泌される各種ペプチド分解酵素の作用に対して耐性を有することが考えられ、高い消化管吸収性も期待できる。 The cyclic dipeptide or salt thereof contained as an active ingredient in the composition of the present invention is high in safety because it is also contained in a heat-treated food protein-derived peptide, and side effects are extremely small compared to conventional pharmaceuticals. Conceivable. In addition, the cyclic dipeptide is excellent in lipophilicity as compared with the linear dipeptide, and high concentration filling into the oily base material is also possible. Therefore, it can be said that the composition of this invention is excellent in the usability in formulation. Furthermore, since cyclic dipeptides are rich in fat solubility and are not dipeptides composed solely of peptide bonds, it is considered that they are resistant to the action of various peptide-degrading enzymes secreted into the digestive tract. Absorbability can also be expected.
　１．カルノシンジペプチダーゼ１及びカルノシンジペプチダーゼ１阻害
　本明細書において「カルノシンジペプチダーゼ１」とは、カルノシン（Ｌ－カルノシン）をβ－アラニンとヒスチジンとに分解することができる血清型のカルノシン分解酵素をいう。カルノシンジペプチダーゼ（カルノシン分解酵素）は、ＣＮＤＰ（carnosine dipeptidase）と省略して表すことができ、また、カルノシナーゼ又はカルノシダーゼとも称される。カルノシンジペプチダーゼには血清（型）カルノシン分解酵素であるＣＮＤＰ１と組織（型）カルノシン分解酵素であるＣＮＤＰ２とが含まれる。これらのうち、本発明で対象とされるカルノシンジペプチダーゼはＣＮＤＰ１であり、ＣＮＤＰ２とは区別される。 1. Carnosine dipeptidase 1 and carnosine dipeptidase 1 inhibition As used herein, “carnosine dipeptidase 1” refers to a serotype carnosine degrading enzyme capable of degrading carnosine (L-carnosine) into β-alanine and histidine. . Carnosine dipeptidase (carnosine degrading enzyme) can be abbreviated as CNDP (carnosine dipeptidase), and is also called carnosinase or carnosidase. Carnosine dipeptidase includes CNDP1 which is a serum (type) carnosine degrading enzyme and CNDP2 which is a tissue (type) carnosine degrading enzyme. Among these, the carnosine dipeptidase targeted in the present invention is CNDP1, which is distinguished from CNDP2.
　本明細書において「カルノシンジペプチダーゼ１阻害」とは、カルノシンジペプチダーゼ１のカルノシン分解活性を阻害することをいう。カルノシンジペプチダーゼ１の阻害作用は、公知の方法に従って評価することができる。例えば、カルノシンとカルノシンジペプチダーゼ１とを接触させるとカルノシンからヒスチジンが生成され、このときヒスチジンの存在によりヒスチジン特有の蛍光が測定可能であることから、その蛍光強度の低下を調べることによりカルノシンジペプチダーゼ１の阻害作用を評価することができる。 As used herein, “carnosine dipeptidase 1 inhibition” refers to inhibiting the carnosine degradation activity of carnosine dipeptidase 1. The inhibitory action of carnosine dipeptidase 1 can be evaluated according to a known method. For example, when carnosine and carnosine dipeptidase 1 are brought into contact with each other, histidine is generated from carnosine, and histidine-specific fluorescence can be measured due to the presence of histidine. Carnosine dipeptidase can be obtained by examining the decrease in fluorescence intensity. 1 inhibitory action can be evaluated.
　２．環状ジペプチド
　本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、アミノ酸のアミノ基とカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する環状ジペプチドのことをいう。そのため、環状ジペプチドは、鎖状のジペプチドとは区別される。なお、本明細書において、環状ジペプチド又はその塩をまとめて、単に、環状ジペプチドと称する場合がある。また、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わず、例えば、〔Cyclo(Met-Arg)〕と〔Cyclo(Arg-Met)〕とは同じ環状ジペプチドを表すものである。 2. Cyclic dipeptide In this specification, “cyclic dipeptide” refers to a cyclic dipeptide having a diketopiperazine structure formed by dehydration condensation of an amino group and a carboxyl group of an amino acid. Say. Therefore, the cyclic dipeptide is distinguished from the chain dipeptide. In addition, in this specification, cyclic dipeptide or its salt may be collectively called a cyclic dipeptide. Further, in this specification, as long as the cyclic dipeptides have the same amino acid configuration, any order thereof may be used, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)] and Represent the same cyclic dipeptide.
　環状ジペプチドではアミド結合を介して二個のアミノ酸の末端部分が結合しているため（即ち、環状ジペプチドは、アミノ末端とカルボキシ末端とがアミド結合することによって形成される環状構造を有しているため）、分子末端部分に極性基であるカルボキシル基やアミノ基が露出している直鎖状ジペプチド（特に、同種のアミノ酸組成からなる直鎖状ジペプチド）と比較して環状ジペプチドは脂溶性が高いという特徴を有する。そのため、環状ジペプチドは直鎖状のジペプチドと比較して、消化管透過性や膜透過性に優れる。このことは、過去に報告されているラット反転腸管を用いた化合物透過試験の結果からも明らかである（J. Pharmacol, 1998, 50: 167-172）。また環状ジペプチドは、その特異的な構造から各種ペプチダーゼに対する耐性も高まると考えられる。 In cyclic dipeptides, the terminal portions of two amino acids are linked via an amide bond (that is, the cyclic dipeptide has a cyclic structure formed by the amide bond between the amino terminus and the carboxy terminus. Therefore, cyclic dipeptides are more lipophilic than linear dipeptides with polar carboxyl groups or amino groups exposed at the molecular end (particularly linear dipeptides of the same amino acid composition). It has the characteristics. Therefore, cyclic dipeptides are superior in gastrointestinal permeability and membrane permeability compared to linear dipeptides. This is also clear from the results of compound permeation tests using rat inverted intestinal tracts reported in the past (J. Pharmacol, 1998, 50: 167-172). Cyclic dipeptides are also considered to have increased resistance to various peptidases due to their specific structure.
　本発明において有効成分として含有される環状ジペプチド又はその塩は、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上のものである。環状ジペプチド又はその塩の数は特に限定されないが、本発明では、上述した環状ジペプチド又はその塩から選択される３つ以上を有効成分とすることが好ましい。また、前記環状ジペプチド又はその塩の中では、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、及びシクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕からなる群から選択される１つ又は２つ以上が好ましく、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、及びシクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕からなる群から選択される１つ又は２つ以上がより好ましい。 Cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention includes cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucine glutamate [Cyclo (Ile-Glu)], cycloisoleuyl lysine [Cyclo ( Ile-Lys)], cycloleucyl tyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleuyl threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine [ Cyclo (Glu-Leu)], cycloarginyl isoleucine (Cyclo (Arg-Ile)), cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cyclo Asparaginyl leucine (Cyclo (Asn-Leu)), cyclomethionyl isoleucine (Cyclo (Met-Ile)), cycloisoleucyl tyrosine (Cyclo (Ile-Tyr)), cyclomethionyl serine (Cyclo (Met-Ser) )], Cyclovalyl Leo Nin [Cyclo (Val-Thr)], cyclovalyl lysine [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyl tyrosine [Cyclo (Tyr-Tyr)] One or more selected from the group. Although the number of cyclic dipeptide or its salt is not specifically limited, In this invention, it is preferable to use 3 or more selected from the cyclic dipeptide mentioned above or its salt as an active ingredient. Among the cyclic dipeptides or salts thereof, cyclotryptophanyl tyrosine [Cyclo (Trp-Tyr)], cycloisoleucillysine [Cyclo (Ile-Lys)], cyclophenylalanyltryptophan [Cyclo (Phe- Trp)], cycloisoleucine threonine (Cyclo (Ile-Thr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclomethionylvaline (Cyclo (Met-Val)), cycloarginylisoleucine (Cyclo (Arg-Ile)], cycloglutamyl leucine [Cyclo (Glu-Leu)], and cyclothreonylglutamic acid [Cyclo (Thr-Glu)], preferably one or more, Tophanyltyrosine [Cyclo (Trp-Tyr)], cycloisoleucine lysine [Cyclo (Ile-Lys)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)], and cycloisoleucylthreonine [Cyclo (Ile-Lys)] -Thr)) One selected from the group or two or more is more preferable.
　本明細書において「環状ジペプチドの塩」とは、前記環状ジペプチドの薬理学的に許容される任意の塩（無機塩及び有機塩を含む）をいい、例えば、前記環状ジペプチドのナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩、塩酸塩、硫酸塩、硝酸塩、燐酸塩、有機酸塩（酢酸塩、クエン酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、乳酸塩、コハク酸塩、フマル酸塩、プロピオン酸塩、蟻酸塩、安息香酸塩、ピクリン酸塩、ベンゼンスルホン酸塩、トリフルオロ酢酸塩等）等が挙げられるが、これらに限定されない。環状ジペプチドの塩は、当該分野で公知の任意の方法により、当業者によって容易に調製され得る。 As used herein, the term “cyclic dipeptide salt” refers to any pharmacologically acceptable salt (including inorganic salts and organic salts) of the cyclic dipeptide, such as sodium salt and potassium salt of the cyclic dipeptide. , Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate , Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, and the like), but are not limited thereto. Cyclic dipeptide salts can be readily prepared by those skilled in the art by any method known in the art.
　本発明で用いる環状ジペプチドは、当該分野で公知の方法に従って調製することができる。例えば、化学合成法や酵素法、微生物発酵法により製造されてもよく、直鎖状ペプチドを脱水及び環化させることにより合成されてもよく、特開２００３－２５２８９６号公報やJournal of Peptide Science, 10, 737-737, 2004に記載の方法に従って調製することもできる。例えば、動植物由来タンパク質を含む原料に酵素処理や熱処理を施して得られる動植物由来ペプチドを、さらに高温加熱処理することで、環状ジペプチドを豊富に含む動植物由来ペプチド熱処理物を得ることができる。これらの点から、本発明で用いる環状ジペプチド又はその塩は、化学的又は生物的に合成されるものであってもよいし、或いは動植物由来ペプチドから得られるものであってもよい。 The cyclic dipeptide used in the present invention can be prepared according to a method known in the art. For example, it may be produced by a chemical synthesis method, an enzymatic method, or a microbial fermentation method, or may be synthesized by dehydration and cyclization of a linear peptide. JP 2003-252896 A, Journal of Peptide や Science, 10, 737-737, 2004. For example, an animal and plant derived peptide heat-treated product rich in cyclic dipeptide can be obtained by further heat-treating an animal and plant derived peptide obtained by subjecting a raw material containing animal and plant derived protein to enzyme treatment or heat treatment. From these points, the cyclic dipeptide or salt thereof used in the present invention may be chemically or biologically synthesized, or may be obtained from an animal or plant derived peptide.
　３．動植物由来ペプチド
　本明細書における「動植物由来ペプチド」は特に限定されないが、例えば、大豆ペプチド、茶ペプチド、麦芽ペプチド、乳ペプチド、プラセンタペプチド、コラーゲンペプチド等を用いることができる。動植物由来のタンパク質又はタンパク質を含む原料から動植物由来ペプチドを調製して用いてもよいが、市販品を用いてもよい。 3. Animal and Plant Derived Peptide “Animal and Plant Derived Peptide” in the present specification is not particularly limited. For example, soybean peptide, tea peptide, malt peptide, milk peptide, placenta peptide, collagen peptide and the like can be used. Animal and plant-derived peptides may be prepared and used from animal or plant-derived proteins or raw materials containing proteins, but commercially available products may also be used.
　３－１．大豆ペプチド
　本明細書でいう「大豆ペプチド」とは、大豆タンパク質に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる低分子ペプチドをいう。原料となる大豆（学名：Glycine max）は品種や産地などの制限なく用いることができ、粉砕品などの加工品段階のものを用いることもできる。 3-1. Soybean peptide As used herein, “soybean peptide” refers to a low molecular weight peptide obtained by subjecting soy protein to enzyme treatment or heat treatment to lower the molecular weight of the protein. Soybeans (scientific name: Glycine max) used as a raw material can be used without restriction of varieties and production areas, and can also be used in processed products such as pulverized products.
　３－２．茶ペプチド
　本明細書でいう「茶ペプチド」とは、茶（茶葉や茶殻を含む）抽出物に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる茶由来の低分子ペプチドをいう。抽出原料となる茶葉としては、茶樹（学名：Camellia sinensis）を用いて製造された茶葉の葉、茎など、抽出して飲用可能な部位を使用することができる。また、その形態も大葉、粉状など制限されない。茶葉の収穫期についても、所望する香味に合わせて適宜選択できる。 3-2. Tea peptide As used herein, “tea peptide” refers to a low molecular weight peptide derived from tea obtained by subjecting a tea (including tea leaves or tea husk) extract to enzyme treatment or heat treatment to lower the protein. . As a tea leaf used as an extraction raw material, a tea leaf (scientific name: Camellia sinensis) manufactured tea leaf leaf, stem, etc. that can be extracted and used can be used. Also, the form is not limited to large leaves or powders. The harvest time of tea leaves can also be selected appropriately according to the desired flavor.
　３－３．麦芽ペプチド
　本明細書でいう「麦芽ペプチド」とは、麦芽又はその粉砕物から得られる抽出物に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる麦芽由来の低分子ペプチドをいう。原料となる麦芽ペプチドは、品種や産地などの制限なく用いることができるが、特に大麦の種子を発芽させた大麦麦芽が好適に用いられる。なお、本明細書においては、大麦麦芽のことを単に麦芽と表記することがある。 3-3. Malt peptide As used herein, the term “malt peptide” refers to a malt-derived low molecular weight peptide obtained by subjecting an extract obtained from malt or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of the protein. . Although the malt peptide used as a raw material can be used without restriction of varieties and production areas, barley malt obtained by germinating barley seeds is particularly preferably used. In the present specification, barley malt may be simply referred to as malt.
　３－４．乳ペプチド
　本明細書でいう「乳ペプチド」とは、天然の乳由来の成分である乳蛋白質をアミノ酸が少なくとも数個結合した分子に分解したものである。より具体的には、ホエイ（乳清タンパク質）又はカゼイン等の乳蛋白質をプロテナーゼ等の酵素により加水分解し、これを濾過して得られる濾液を殺菌及び／又は濃縮して乾燥することにより得られるホエイペプチド、カゼインペプチド等が挙げられる。 3-4. Milk peptide As used herein, “milk peptide” is a product obtained by decomposing milk protein, which is a component derived from natural milk, into a molecule in which at least several amino acids are bound. More specifically, it is obtained by hydrolyzing milk protein such as whey (whey protein) or casein with an enzyme such as proteinase, and filtering and sterilizing and / or concentrating and drying the filtrate. Examples include whey peptides and casein peptides.
　３－５．プラセンタペプチド
　プラセンタとは哺乳類の胎盤のことであり、その優れた機能性から、近年、健康食品、化粧品、医薬品素材として用いられている。本明細書において「プラセンタペプチド」とは、プラセンタを酵素処理、又は亜臨界処理により可溶化、低分子化したものをいう。また、本来の意味とは異なるが、植物の胎座から得られる抽出物が胎盤由来のプラセンタと同等の生理学的効果を有するものとして健康食品、化粧品等に利用されており、これらは植物プラセンタと呼ばれる。本明細書における「プラセンタペプチド」には、植物プラセンタに酵素処理、又は亜臨界処理等を施し、可溶化、低分子化したものも含まれる。 3-5. The placenta peptide placenta is the placenta of mammals and has been used as a health food, cosmetics, and pharmaceutical material in recent years because of its excellent functionality. In the present specification, “placenta peptide” refers to a placenta that has been solubilized and reduced in molecular weight by enzyme treatment or subcritical treatment. In addition, although different from the original meaning, extracts obtained from plant placenta are used in health foods, cosmetics, etc. as having a physiological effect equivalent to placenta derived from placenta. be called. The “placenta peptide” in the present specification includes those obtained by subjecting plant placenta to enzyme treatment or subcritical treatment, solubilization and low molecular weight.
　３－６．コラーゲンペプチド
　本明細書でいう「コラーゲンペプチド」とは、コラーゲン又はその粉砕物を酵素処理や熱処理を施し、コラーゲンを低分子化することによって得られる低分子ペプチドをいう。コラーゲンは動物の結合組織の主要なタンパク質であり、ヒトを含めた哺乳類の身体に最も大量に含まれるタンパク質である。 3-6. Collagen peptide As used herein, the term “collagen peptide” refers to a low molecular peptide obtained by subjecting collagen or a pulverized product thereof to enzymatic treatment or heat treatment to lower the molecular weight of collagen. Collagen is a major protein in animal connective tissue and is the most abundant protein in mammalian bodies including humans.
　４．動植物由来ペプチド熱処理物
　上述した通り、動植物由来ペプチドを高温加熱処理することで、環状ジペプチドを豊富に含む動植物由来ペプチド熱処理物を得ることができる。本明細書において「高温加熱処理」とは、１００℃以上の温度かつ大気圧を超える圧力下で一定時間処理することを意味する。高温高圧処理装置としては、耐圧性抽出装置や圧力鍋、オートクレーブなどを条件に合わせて用いることができる。 4). As described above animal and plant derived peptides Cook, by high-temperature heat treatment plants and animals derived peptides, it is possible to obtain plants and animals derived peptides heat treatment comprising a cyclic dipeptide rich. In this specification, “high temperature heat treatment” means that the treatment is performed for a certain period of time at a temperature of 100 ° C. or higher and a pressure exceeding atmospheric pressure. As the high-temperature and high-pressure treatment device, a pressure-resistant extraction device, a pressure cooker, an autoclave, or the like can be used according to conditions.
　高温加熱処理における温度は、１００℃以上である限り特に限定されないが、好ましくは１００℃～１７０℃、より好ましくは１１０℃～１５０℃、さらにより好ましくは１２０℃～１４０℃である。なお、この温度は、加熱装置として耐圧性抽出装置を用いた場合には抽出カラムの出口温度を測定した値を示し、加熱装置としてオートクレーブを用いた場合には、圧力容器内の中心温度の温度を測定した値を示す。 The temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, but is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, and still more preferably 120 ° C to 140 ° C. In addition, this temperature shows the value which measured the exit temperature of the extraction column, when using a pressure-resistant extraction apparatus as a heating apparatus, and when using an autoclave as a heating apparatus, it is the temperature of the center temperature in a pressure vessel. The measured value is shown.
　高温加熱処理における圧力は、大気圧を超える圧力である限り特に限定されないが、好ましくは０．１０１ＭＰａ～０．７９ＭＰａ、より好ましくは０．１０１ＭＰａ～０．６０ＭＰａ、さらにより好ましくは０．１０１ＭＰａ～０．４８ＭＰａである。 The pressure in the high-temperature heat treatment is not particularly limited as long as it is a pressure exceeding atmospheric pressure, but is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, and even more preferably 0.101 MPa to 0. 48 MPa.
　高温加熱処理時間は、環状ジペプチドを含む処理物が得られる限り特に限定されないが、好ましくは１５分～６００分程度、より好ましくは３０分～５００分程度、さらにより好ましくは６０分～３００分程度である。 The high-temperature heat treatment time is not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably about 60 minutes to 300 minutes. It is.
　また、動植物由来ペプチドの高温加熱処理条件は、環状ジペプチドを含む処理物が得られる限り特に限定されないが、好ましくは［温度：圧力：時間］が［１００℃～１７０℃：０．１０１ＭＰａ～０．７９ＭＰａ：１５分～６００分］、より好ましくは［１１０℃～１５０℃：０．１０１ＭＰａ～０．６０ＭＰａ：３０分～５００分］、さらにより好ましくは［１２０℃～１４０℃：０．１０１ＭＰａ～０．４８ＭＰａ：６０分～３００分］である。 In addition, the high-temperature heat treatment conditions for the animal and plant derived peptides are not particularly limited as long as a processed product containing a cyclic dipeptide is obtained, but preferably [temperature: pressure: time] is [100 ° C. to 170 ° C .: 0.101 MPa to 0.001. 79 MPa: 15 minutes to 600 minutes], more preferably [110 ° C. to 150 ° C .: 0.101 MPa to 0.60 MPa: 30 minutes to 500 minutes], even more preferably [120 ° C. to 140 ° C .: 0.101 MPa to 0 48 MPa: 60 minutes to 300 minutes].
　なお、得られた動植物由来ペプチド熱処理物に対して、所望により、濾過、遠心分離、濃縮、限外濾過、凍結乾燥、粉末化等の処理を行ってもよい。また、動植物由来ペプチド熱処理物中の特定の環状ジペプチドが所望の含有量に満たなければ、不足する特定の環状ジペプチドについては他の動植物由来ペプチドや市販品、合成品を用いて適宜追加することもできる。 In addition, you may perform processes, such as filtration, centrifugation, concentration, ultrafiltration, lyophilization | freeze-drying, and powdering, with respect to the obtained heat-processed peptide derived from animals and plants. In addition, if the specific cyclic dipeptide in the heat-treated product of animal and plant derived peptides does not satisfy the desired content, the specific cyclic dipeptide that is deficient may be appropriately added using other animal or plant derived peptides, commercial products, or synthetic products. it can.
　５．カルノシンジペプチダーゼ１阻害用組成物
　５－１．環状ジペプチド含有カルノシンジペプチダーゼ１阻害用組成物
　本発明の一態様は、特定の環状ジペプチド又はその塩を有効成分として含むカルノシンジペプチダーゼ１阻害用組成物である。 5). Composition for inhibiting carnosine dipeptidase 1 5-1. Composition for inhibiting carnosine dipeptidase 1 containing cyclic dipeptide One embodiment of the present invention is a composition for inhibiting carnosine dipeptidase 1 comprising a specific cyclic dipeptide or a salt thereof as an active ingredient.
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として含むものである。本発明のカルノシンジペプチダーゼ１阻害用組成物に含まれる環状ジペプチド又はその塩の数は特に限定されないが、本発明では、上述した環状ジペプチド又はその塩から選択される３つ以上が含まれることが好ましい。前記環状ジペプチド又はその塩の中では、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、及びシクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕からなる群から選択される１つ又は２つ以上が好ましく、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、及びシクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕からなる群から選択される１つ又は２つ以上がより好ましい。 The composition for inhibiting carnosine dipeptidase 1 of the present invention comprises cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamate [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys). )], Cycloleucyl tyrosine [Cyclo (Leu-Tyr)], cyclomethionyl valine [Cyclo (Met-Val)], cycloisoleucil threonine [Cyclo (Ile-Thr)], cycloglutamyl leucine [Cyclo (Glu -Leu)], cycloarginylisoleucine [Cyclo (Arg-Ile)], cyclotryptophanyltyrosine [Cyclo (Trp-Tyr)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)], cycloasparaginyl Leucine (Cyclo (Asn-Leu)), cyclomethionyl isoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), Cyclovalylthreonine (Cyclo (Val-Thr) Or one or two selected from the group consisting of cyclovalyllysine [Cyclo (Val-Lys)], cyclothreonylglutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] It contains one or more cyclic dipeptides or salts thereof as active ingredients. The number of cyclic dipeptides or salts thereof contained in the composition for inhibiting carnosine dipeptidase 1 of the present invention is not particularly limited, but the present invention may include three or more selected from the above-mentioned cyclic dipeptides or salts thereof. preferable. Among the cyclic dipeptides or salts thereof, cyclotryptophanyl tyrosine [Cyclo (Trp-Tyr)], cycloisoleucillysine [Cyclo (Ile-Lys)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)] ), Cycloisoleucine threonine [Cyclo (Ile-Thr)], cyclomethionylserine [Cyclo (Met-Ser)], cyclomethionylvaline [Cyclo (Met-Val)], cycloarginylisoleucine [Cyclo (Arg) -Ile)], cycloglutamyl leucine [Cyclo (Glu-Leu)], and cyclothreonylglutamic acid [Cyclo (Thr-Glu)], preferably one or two or more, cyclotryptophanyl Tyrosine (Cyclo (Trp-Tyr)), cycloisoleucine lysine (Cyclo (Ile-Lys)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), and cycloisoleucil threonine [Cyclo (Ile-Thr) )] One selected or two or more is more preferable.
　本発明のカルノシンジペプチダーゼ１阻害用組成物における環状ジペプチド又はその塩の含有量は、その投与形態、投与方法などを考慮し、本発明の所望の効果が得られるような量であればよく、特に限定されるものではない。例えば、大豆ペプチド、茶ペプチド、麦芽ペプチド、乳ペプチド、プラセンタペプチド、又はコラーゲンペプチドを原料として用いる場合、本発明のカルノシンジペプチダーゼ１阻害用組成物におけるシクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、シクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕、又はそれぞれに対応する塩の含有量としては、２．０ｐｐｍ／Ｂｒｉｘ（２００μｇ／１００ｇ／Ｂｘ）以上、好ましくは１０ｐｐｍ／Ｂｒｉｘ以上、より好ましくは２０ｐｐｍ／Ｂｒｉｘ以上であり、８０００ｐｐｍ／Ｂｒｉｘ以下、好ましくは８００ｐｐｍ／Ｂｒｉｘ以下、より好ましくは８０ｐｐｍ／Ｂｒｉｘ以下であり、典型的には、２．０～８０００ｐｐｍ／Ｂｒｉｘ、好ましくは１０～８００ｐｐｍ／Ｂｒｉｘ、より好ましくは２０～８０ｐｐｍ／Ｂｒｉｘである。前記の含有量は、合成品又は精製品の環状ジペプチド又はその塩を用いた場合にも適用可能である。本発明において、環状ジペプチド又はその塩の含有量は上記の通りＢｒｉｘ（ブリックス：Ｂｘ）あたりの量で表される。本明細書において「Ｂｒｉｘあたりの量」は、２０℃のショ糖溶液（ショ糖のみを溶質として含む水溶液）の質量百分率に相当する値で定められる量を意味する。なお、特に断りがない限り、本明細書において用いる「ｐｐｍ」は、重量／容量（ｗ／ｖ）のｐｐｍを意味し、１．０ｐｐｍ／Ｂｒｉｘは溶媒の比重が１の場合、０．１ｍｇ／ｍＬと換算され、０．０１重量％と換算されるものである。 The content of the cyclic dipeptide or the salt thereof in the composition for inhibiting carnosine dipeptidase 1 of the present invention may be an amount that can achieve the desired effect of the present invention in consideration of its administration form, administration method, etc. It is not particularly limited. For example, when soy peptide, tea peptide, malt peptide, milk peptide, placenta peptide, or collagen peptide is used as a raw material, cyclolysyl lysine [Cyclo (Lys-Lys)] in the composition for inhibiting carnosine dipeptidase 1 of the present invention, Cycloisoleucylglutamic acid (Cyclo (Ile-Glu)), cycloisoleucillysine (Cyclo (Ile-Lys)), cycloleucyltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met- Val)), cycloisoleuyl threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloarginyl isoleucine (Cyclo (Arg-Ile)), cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)], cycloasparaginyl leucine [Cyclo (Asn-Leu)], cyclomethionyl isoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)), cyclovalyl The content of lysine [Cyclo (Val-Lys)], cyclothreonylglutamic acid [Cyclo (Thr-Glu)], cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)], or a salt corresponding to each, is 2. 0 ppm / Brix (200 μg / 100 g / Bx) or more, preferably 10 ppm / Brix or more, more preferably 20 ppm / Brix or more, 8000 ppm / Brix or less, preferably 800 ppm / Brix or less, more preferably 80 ppm / Brix or less. , Typically 2.0 to 8000 ppm / Brix, preferably 10 to 800 ppm / Brix, more preferably 20 to 80 ppm / Brix. It is. The above content can also be applied when a synthetic or purified cyclic dipeptide or a salt thereof is used. In this invention, content of cyclic dipeptide or its salt is represented by the quantity per Brix (Brix: Bx) as above-mentioned. In this specification, “amount per Brix” means an amount determined by a value corresponding to a mass percentage of a sucrose solution at 20 ° C. (an aqueous solution containing only sucrose as a solute). Unless otherwise specified, “ppm” used in the present specification means ppm of weight / volume (w / v), and 1.0 ppm / Brix is 0.1 mg / wt when the specific gravity of the solvent is 1. Converted to mL and converted to 0.01% by weight.
　環状ジペプチド又はその塩の含有量は、公知の方法に従って測定することができる。例えば、ＬＣ－ＭＳ／ＭＳ又は糖度計を用いて測定することができる。 The content of the cyclic dipeptide or a salt thereof can be measured according to a known method. For example, it can be measured using LC-MS / MS or a saccharimeter.
　５－２．作用メカニズム
　上述した通り、カルノシンジペプチダーゼ１が阻害されることで、カルノシンジペプチダーゼ１により分解されるカルノシンのヒト等の哺乳動物における体内濃度が維持、又は当該濃度の低下が抑制される。カルノシンの作用としては、プロトンバッファーリング活性、カルシウム分泌とカルシウム感受性制御、抗酸化作用、金属イオンキレート作用、ヒスチジン／ヒスタミンの細胞外供与体、高血糖改善作用、抗炎症作用、終末糖化産物の生成抑制、脳虚血による細胞死の抑制、アルツハイマー病（ＡＤ）モデルマウスにおけるアミロイドβの蓄積作用、免疫調節作用等が挙げられる。そのため、カルノシンの体内濃度を高く保持することによって、アミロイドβの蓄積作用に基づいて統合失調症などに伴う認知機能低下やアルツハイマー、自閉症の予防又は改善効果が得られ、高血糖改善作用に基づいて糖尿病又は酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患発症の予防又は改善効果が得られ、抗炎症作用に基づいて血管や組織の炎症の予防又は改善効果が得られ、免疫調節作用に基づいて免疫機能低下の予防又は改善効果が得られる。 5-2. Mechanism of Action As described above, inhibition of carnosine dipeptidase 1 maintains the body concentration of carnosine degraded by carnosine dipeptidase 1 in mammals such as humans, or suppresses a decrease in the concentration. Carnosine functions include proton buffering activity, calcium secretion and calcium sensitivity control, antioxidant action, metal ion chelate action, extracellular donor of histidine / histamine, hyperglycemia improvement action, anti-inflammatory action, generation of advanced glycation end products Examples thereof include suppression, suppression of cell death due to cerebral ischemia, accumulation of amyloid β, immunoregulation in Alzheimer's disease (AD) model mice, and the like. Therefore, by maintaining carnosine concentration in the body, it is possible to prevent or improve cognitive function associated with schizophrenia, Alzheimer's, or autism based on the accumulation of amyloid β. Based on this, it is possible to prevent or ameliorate the onset of various diseases caused by diabetes or oxidative stress or the production of advanced glycation end products. Based on the above, a preventive or ameliorating effect on immune function decline is obtained.
　５－３．他の成分
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、その形態に応じて、環状ジペプチド又はその塩の他に、任意の添加剤や通常用いられる任意の成分を含有することができる。これらの添加剤及び／又は成分の例としては、ビタミンＥ、ビタミンＣ等のビタミン類、ミネラル類、栄養成分、香料などの生理活性成分の他、製剤化において配合される賦形剤、結合剤、乳化剤、緊張化剤（等張化剤）、緩衝剤、溶解補助剤、防腐剤、安定化剤、抗酸化剤、着色剤、凝固剤、又はコーティング剤等が挙げられるが、これらに限定されるものではない。 5-3. Other Components The composition for inhibiting carnosine dipeptidase 1 of the present invention can contain any additive and any commonly used component in addition to the cyclic dipeptide or a salt thereof, depending on its form. Examples of these additives and / or ingredients include vitamins such as vitamin E and vitamin C, bioactive ingredients such as minerals, nutritional ingredients, and fragrances, as well as excipients and binders incorporated in the formulation. , Emulsifiers, tonicity agents (isotonic agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, colorants, coagulants, or coating agents, but are not limited thereto. It is not something.
　５－４．用途
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、前述の環状ジペプチド又はその塩を有効成分として含有することを特徴としており、当該環状ジペプチド又はその塩がカルノシンジペプチダーゼ１の活性を阻害して、カルノシンジペプチダーゼ１により分解されるカルノシンの体内濃度が維持、又は当該濃度の低下が抑制される。体内においてカルノシンが高い濃度で保持されることで、認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善を効果的に行うことができる。従って、本発明の組成物は、認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善用のカルノシンジペプチダーゼ１阻害用組成物である。これらの用途に基づき、本発明のカルノシンジペプチダーゼ１阻害用組成物は、認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善用組成物ともなり得る。なお、本明細書において「予防又は改善」には、現在の状態をより良い状態にすることと現在の状態よりも悪い状態になることを防ぐこととの両方の概念が包含されることから、治療、回復、軽減、緩和等の用語もこれに含まれ得る。 5-4. Use The composition for inhibiting carnosine dipeptidase 1 of the present invention is characterized by containing the aforementioned cyclic dipeptide or a salt thereof as an active ingredient, and the cyclic dipeptide or a salt thereof inhibits the activity of carnosine dipeptidase 1. The in vivo concentration of carnosine decomposed by carnosine dipeptidase 1 is maintained, or a decrease in the concentration is suppressed. Carnosine is maintained at a high concentration in the body, thereby reducing cognitive function, diabetes, immune function, vascular or tissue inflammation, oxidative stress, or production of advanced glycation end products, Alzheimer's disease, or autism Prevention or improvement can be carried out effectively. Therefore, the composition of the present invention is used for the prevention or improvement of various diseases, Alzheimer's, or autism resulting from the production of cognitive function decline, diabetes, immune function decline, vascular or tissue inflammation, oxidative stress or advanced glycation end products. This is a composition for inhibiting carnosine dipeptidase 1. Based on these uses, the composition for inhibiting carnosine dipeptidase 1 of the present invention is used for various diseases caused by cognitive decline, diabetes, immune function decline, vascular or tissue inflammation, oxidative stress or production of advanced glycation end products, Alzheimer's Or a composition for preventing or ameliorating autism. In the present specification, “prevention or improvement” includes both concepts of making the current state a better state and preventing the current state from becoming worse than the current state. Terms such as treatment, recovery, alleviation, alleviation can also be included.
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、公知の方法に従って、錠剤（被覆錠剤を含む）、顆粒剤、散剤、粉末剤、又はカプセル剤等の固形剤や、通常液剤、懸濁剤、又は乳剤等の液剤等に製剤化することができる。これらの組成物はそのまま水等と共に服用することができる。また、容易に配合することが出来る形態（例えば、粉末形態や顆粒形態）に調製後、例えば、医薬品の原材料として用いることができる。 The composition for inhibiting carnosine dipeptidase 1 of the present invention is prepared by a known method in the form of a solid agent such as a tablet (including a coated tablet), a granule, a powder, a powder, or a capsule, a normal solution, a suspension, Alternatively, it can be formulated into a liquid such as an emulsion. These compositions can be taken with water or the like as it is. Moreover, after preparing the form (for example, powder form and granule form) which can be mix | blended easily, it can use, for example as a raw material of a pharmaceutical.
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、或いは当該剤を含む組成物として提供することもできる。本発明の組成物としては、医薬組成物、飲食品組成物、食品組成物、飲料組成物、化粧用組成物等が挙げられるが、これらに限定されない。食品組成物の限定的でない例として、機能性食品、健康補助食品、栄養機能食品、特別用途食品、特定保健用食品、栄養補助食品、食事療法用食品、健康食品、サプリメント、食品添加剤等が挙げられる。 The composition for inhibiting carnosine dipeptidase 1 of the present invention can be provided in the form of an agent as an example, but is not limited to this form. The agent can be provided as a composition as it is or as a composition containing the agent. Examples of the composition of the present invention include, but are not limited to, a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like. Non-limiting examples of food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、治療的用途（医療用途）又は非治療用途（非医療用途）のいずれにも適用することができる。具体的には、医薬品、医薬部外品及び化粧料等や薬事法上はこれらに属さないが、認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善効果等を明示的又は暗示的に訴求する組成物としての使用が挙げられる。 The composition for inhibiting carnosine dipeptidase 1 of the present invention can be applied to any therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it does not belong to pharmaceuticals, quasi drugs, cosmetics, etc. or the Pharmaceutical Affairs Law, but cognitive function decline, diabetes, immune function decline, inflammation of blood vessels or tissues, oxidative stress or production of advanced glycation end products Use as a composition that explicitly or implicitly promotes various diseases, Alzheimer's, or the prevention or amelioration effect of autism.
　本発明は、別の側面では、カルノシンジペプチダーゼ１阻害により発揮される機能の表示を付した、前記カルノシンジペプチダーゼ１阻害用組成物に関する。このような表示又は機能性表示は特に限定されないが、例えば、「認知機能の低下を抑制する」、「認知機能の維持を期待する」、「血糖値の上昇を抑制する」、「免疫機能を高める」、「抗酸化作用を期待する」、「酸化ストレスを低減する」、「抗糖化作用を期待する」、「糖化ストレスを低減する」、「血管の炎症を抑制する」、「アルツハイマー症の予防若しくは改善を期待する」、「自閉症の予防若しくは改善を期待する」等、或いは、これらと同視できる表示又は機能性表示が挙げられる。本明細書において、当該表示及び機能性表示のような表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 In another aspect, the present invention relates to the composition for inhibiting carnosine dipeptidase 1, which is labeled with the function exhibited by carnosine dipeptidase 1 inhibition. Such a display or functional display is not particularly limited, but for example, “suppress cognitive function decrease”, “expect cognitive function maintenance”, “suppress blood glucose level increase”, “immune function ”Enhance”, “antioxidant”, “reduce oxidative stress”, “anti-glycation”, “reduce glycation stress”, “suppress vascular inflammation”, “alzheimer's disease” Examples such as “expect prevention or improvement”, “expect prevention or improvement of autism”, etc., or display or functional indication that can be equated with these. In the present specification, indications such as the indication and the functionality indication may be attached to the composition itself, or may be attached to a container or packaging of the composition.
　本発明のカルノシンジペプチダーゼ１阻害用組成物は、その形態に応じた適当な方法で摂取することができる。摂取方法は、本発明に係る環状ジペプチド又はその塩が循環血中に移行できるのであれば特に限定はない。例えば、経口用固形製剤、内服液剤若しくはシロップ剤等の経口用液体製剤、又は注射剤、外用剤、坐剤若しくは経皮吸収剤等の非経口用製剤などの形態とすることができるが、これらに限定されない。なお、本明細書において「摂取」とは、摂取、服用、又は飲用等の全態様を含むものとして用いられる。 The composition for inhibiting carnosine dipeptidase 1 of the present invention can be ingested by an appropriate method according to the form. The intake method is not particularly limited as long as the cyclic dipeptide or a salt thereof according to the present invention can be transferred into the circulating blood. For example, oral solid preparations, oral liquid preparations such as internal liquids or syrups, or parenteral preparations such as injections, external preparations, suppositories or transdermal absorption agents can be used. It is not limited to. In the present specification, “ingestion” is used to include all aspects such as ingestion, taking, or drinking.
　本発明のカルノシンジペプチダーゼ１阻害用組成物の適用量は、その形態、投与方法、使用目的及び投与対象である患者又は患獣の年齢、体重、症状によって適宜設定され、一定ではない。本発明の組成物の有効ヒト摂取量は一定ではないが、例えば、その有効成分である環状ジペプチド又はその塩の重量として、体重５０ｋｇのヒトで一日あたり、好ましくは１０ｍｇ以上、より好ましくは１００ｍｇ以上である。また、投与は所望の投与量範囲内において、１日内において単回又は数回に分けて行ってもよい。投与期間も任意である。なお、本発明の組成物の有効ヒト摂取量とは、ヒトにおいて有効な効果を示す本発明のカルノシンジペプチダーゼ１阻害用組成物の摂取量のことであり、当該組成物に含まれる環状ジペプチドの種類は特に限定されない。 The application amount of the composition for inhibiting carnosine dipeptidase 1 of the present invention is appropriately set depending on the form, administration method, purpose of use, and age, weight and symptom of the patient or animal to be administered, and is not constant. Although the effective human intake of the composition of the present invention is not constant, for example, the weight of the cyclic dipeptide or salt thereof as the active ingredient is preferably 10 mg or more, more preferably 100 mg per day for a human body weight of 50 kg. That's it. Further, administration may be performed once or several times within one day within a desired dose range. The administration period is also arbitrary. The effective human intake of the composition of the present invention refers to the intake of the composition for inhibiting carnosine dipeptidase 1 of the present invention that exhibits an effective effect in humans, and the cyclic dipeptide contained in the composition The type is not particularly limited.
　本発明のカルノシンジペプチダーゼ１阻害用組成物の適用対象は、好ましくはヒトであるが、ウシ、ウマ、ヤギ等の家畜動物、イヌ、ネコ、ウサギ等のペット動物、又は、マウス、ラット、モルモット、サル等の実験動物であってもよい。ヒト以外の動物を対象に投与する場合、マウス１個体当たり約２０ｇに対して１日あたりの使用量は、組成物中の有効成分の含有量、適用対象者の状態、体重、性別及び年齢等の条件により異なるが、通常、環状ジペプチド又はその塩の総配合量として、好ましくは１０ｍｇ／ｋｇ以上、より好ましくは１００ｍｇ／ｋｇ以上を摂取できる量にするとよい。 The subject of application of the composition for inhibiting carnosine dipeptidase 1 of the present invention is preferably human, but domestic animals such as cattle, horses and goats, pet animals such as dogs, cats and rabbits, or mice, rats and guinea pigs. Or a laboratory animal such as a monkey. When a non-human animal is administered to a subject, the amount used per day for about 20 g per mouse is the content of the active ingredient in the composition, the state of the subject, weight, sex, age, etc. Usually, the total amount of the cyclic dipeptide or its salt is preferably 10 mg / kg or more, more preferably 100 mg / kg or more.
　５－５．カルノシンとの組み合わせ（併用）
　上述した特定の環状ジペプチド又はその塩は、カルノシンと併用することができる。そのため本発明は、一つの態様として、上述した特定の環状ジペプチド又はその塩とカルノシンとを組み合わせてなる組成物（以下、「本発明の併用組成物」とも称する）を提供することができる。 5-5. Combination with carnosine (combination)
The specific cyclic dipeptide described above or a salt thereof can be used in combination with carnosine. Therefore, this invention can provide the composition (henceforth "the combined use composition of this invention") which combined the specific cyclic dipeptide mentioned above or its salt, and carnosine as one aspect.
　上記の環状ジペプチド又はその塩とカルノシンとを組み合わせて用いることによって、当該環状ジペプチド又はその塩のカルノシンジペプチダーゼ１阻害作用がカルノシンジペプチダーゼ１からのカルノシンの分解を遅延させ、標的とする組織や器官に効果的に当該カルノシンを送達することができる。体内に元来存在しているカルノシンのみならず、カルノシンジペプチダーゼ１阻害用組成物とカルノシンとを併用することで、体内のカルノシン濃度をより高く維持することができ、カルノシンの作用を効果的に増強させることができる。 By using a combination of the above cyclic dipeptide or a salt thereof and carnosine, the carnosine dipeptidase 1 inhibitory action of the cyclic dipeptide or a salt thereof delays the degradation of carnosine from carnosine dipeptidase 1, and targets tissues and organs. Can effectively deliver the carnosine. In addition to carnosine originally present in the body, the carnosine concentration in the body can be maintained higher by combining carnosine with a composition for inhibiting carnosine dipeptidase 1 so that the action of carnosine is effectively improved. Can be enhanced.
　本発明の併用組成物は、上述した特定の環状ジペプチド又はその塩を含むことからカルノシンジペプチダーゼ１阻害用組成物となり得る。また、本発明の併用組成物は、カルノシン作用効果の増強という観点から、上記５－４で説明した用途に用いることが好ましい。即ち、本発明の併用組成物は、好ましくは、認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善用組成物である。本発明の併用組成物は、医薬組成物、飲食品組成物、食品組成物、飲料組成物、化粧用組成物等とすることができるが、これらに限定されない。食品組成物の限定的でない例として、機能性食品、健康補助食品、栄養機能食品、特別用途食品、特定保健用食品、栄養補助食品、食事療法用食品、健康食品、サプリメント、食品添加剤等が挙げられる。 The combined composition of the present invention can be a composition for inhibiting carnosine dipeptidase 1 because it contains the above-mentioned specific cyclic dipeptide or a salt thereof. In addition, the combination composition of the present invention is preferably used for the uses described in 5-4 above from the viewpoint of enhancing the carnosine effect. That is, the combination composition of the present invention is preferably used for various diseases, Alzheimer's disease, or autism caused by cognitive decline, diabetes, immune function decline, blood vessel or tissue inflammation, oxidative stress or production of advanced glycation end products. It is a composition for prevention or improvement. The combination composition of the present invention can be a pharmaceutical composition, a food / beverage product composition, a food composition, a beverage composition, a cosmetic composition, and the like, but is not limited thereto. Non-limiting examples of food compositions include functional foods, health supplements, functional nutrition foods, special foods, foods for specified health use, dietary supplements, diet foods, health foods, supplements, food additives, etc. Can be mentioned.
　本発明におけるカルノシンはβ－アラニンとヒスチジンとで構成されるジペプチドであり、β－アラニルヒスチジンとも称する。カルノシンには、Ｄ体（Ｄ－カルノシン）、Ｌ体（Ｌ－カルノシン）及びＤＬ体（ＤＬ－カルノシン）のいずれもが含まれるが、本発明では、好ましくはＬ体（Ｌ－カルノシン）及びＤＬ体（ＤＬ－カルノシン）、より好ましくはＬ体（Ｌ－カルノシン）である。なお、Ｄ体（Ｄ－カルノシン）のＣＡＳ登録番号は５８５３－００－９であり、Ｌ体（Ｌ－カルノシン）のＣＡＳ登録番号は３０５－８４－０である。 Carnosine in the present invention is a dipeptide composed of β-alanine and histidine and is also referred to as β-alanyl histidine. Carnosine includes all of D-form (D-carnosine), L-form (L-carnosine), and DL-form (DL-carnosine). In the present invention, preferably L-form (L-carnosine) and DL-form. The body (DL-carnosine), more preferably the L body (L-carnosine). The CAS registration number of D-form (D-carnosine) is 5853-00-9, and the CAS registration number of L-form (L-carnosine) is 305-84-0.
　本発明において用いられるカルノシンは、その入手方法については特に限定されず、動物に由来する天然のもの、或いは化学合成法等により得られるもののいずれであってもよい。本発明では、好適には市販されているカルノシンが使用される。また、本発明の併用組成物におけるカルノシンの含有量は、その投与形態、投与方法などを考慮し、本発明の所望の効果が得られるような量であればよく、特に限定されるものではない。 The method of obtaining carnosine used in the present invention is not particularly limited, and may be any natural one derived from animals or one obtained by chemical synthesis. In the present invention, commercially available carnosine is preferably used. In addition, the content of carnosine in the combination composition of the present invention is not particularly limited as long as the desired effect of the present invention is obtained in consideration of the administration form, administration method, and the like. .
　本発明の併用組成物における上記の環状ジペプチド又はその塩とカルノシンとの量比は、本発明の所望の効果が得られるような比であればよく、特に限定されるものではない。例えば、本発明の併用組成物における当該比（環状ジペプチド又はその塩：カルノシン）は、重量比として、例えば１：１０００～１：１、好ましくは１：９５０～１：５、より好ましくは１：９００～１：１０である。 The amount ratio of the above-mentioned cyclic dipeptide or a salt thereof and carnosine in the combination composition of the present invention is not particularly limited as long as the desired effect of the present invention is obtained. For example, the ratio (cyclic dipeptide or a salt thereof: carnosine) in the combination composition of the present invention is, for example, 1: 1000 to 1: 1, preferably 1: 950 to 1: 5, more preferably 1: 900 to 1:10.
　６．カルノシンジペプチダーゼ１を阻害するための環状ジペプチド又はその塩の使用
　本発明の一態様は、アミノ酸を構成単位とする特定の環状ジペプチド又はその塩のカルノシンジペプチダーゼ１を阻害するための使用である。好ましくは、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩のカルノシンジペプチダーゼ１を阻害するための使用である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むもののカルノシンジペプチダーゼ１を阻害するための使用である。 6). Use of a cyclic dipeptide or a salt thereof for inhibiting carnosine dipeptidase 1 One aspect of the present invention is the use of a specific cyclic dipeptide or a salt thereof having amino acid as a constituent unit for inhibiting carnosine dipeptidase 1. Preferably, cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucyl glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucyl tyrosine [Cyclo ( Leu-Tyr)], cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloarginyl isoleucine [ Cyclo (Arg-Ile)], cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyl tryptophan (Cyclo (Phe-Trp)), cycloasparaginyl leucine (Cyclo (Asn-Leu)), Cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucil tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)) ), Cyclovalyl lysine (Cyclo (Val-Lys)), Carnosine dipeptidase 1 of one or more cyclic dipeptides or salts thereof selected from the group consisting of rotreonylglutamic acid [Cyclo (Thr-Glu)] and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] It is used for inhibiting. More preferably, it is a use for inhibiting carnosine dipeptidase 1 comprising at least three selected from the cyclic dipeptides or salts thereof.
　本発明の使用には、例えば、認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善するための、前記環状ジペプチド又はその塩の使用が含まれるが、これらに限定されるものではない。また、当該使用は、ヒト又は非ヒト動物における使用であり、治療的使用であっても非治療的使用であってもよい。ここで、「非治療的」とは、医療行為、即ち、治療による人体への処理行為を含まない概念である。 In the use of the present invention, for example, prevention or improvement of various diseases, Alzheimer's, or autism resulting from production of cognitive decline, diabetes, immune decline, vascular or tissue inflammation, oxidative stress or advanced glycation end products, etc. For this purpose, the use of the cyclic dipeptide or a salt thereof is included, but is not limited thereto. In addition, the use is a use in a human or non-human animal, and may be a therapeutic use or a non-therapeutic use. Here, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by treatment.
　７．カルノシンジペプチダーゼ１を阻害する方法
　本発明の一態様は、アミノ酸を構成単位とする特定の環状ジペプチド又はその塩を有効成分として使用する、カルノシンジペプチダーゼ１を阻害する方法である。当該方法は、好ましくは、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として使用することを含む、カルノシンジペプチダーゼ１を阻害する方法である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものを有効成分として使用することを含む、カルノシンジペプチダーゼ１を阻害する方法である。 7). Method for Inhibiting Carnosine Dipeptidase 1 One embodiment of the present invention is a method for inhibiting carnosine dipeptidase 1 using a specific cyclic dipeptide having amino acid as a constituent unit or a salt thereof as an active ingredient. The method is preferably cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], Tyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cyclo Arginylisoleucine [Cyclo (Arg-Ile)], cyclotryptophanyltyrosine [Cyclo (Trp-Tyr)], cyclophenylalanyltryptophan [Cyclo (Phe-Trp)], cycloasparaginylleucine [Cyclo (Asn- Leu)], cyclomethionyl isoleucine (Cyclo (Met-Ile)), cycloisoleucil tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo ( Val-Thr)), cyclovallyricin (Cyclo (V al-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)], or one or more cyclic dipeptides thereof A method for inhibiting carnosine dipeptidase 1 comprising using a salt as an active ingredient. More preferably, it is a method for inhibiting carnosine dipeptidase 1, which comprises using as an active ingredient a substance containing three or more selected from the cyclic dipeptides or salts thereof.
　当該方法に関する別の態様は、カルノシンジペプチダーゼ１の阻害を必要とする対象に、特定の環状ジペプチド又はその塩を有効成分として治療有効量を投与することを含む、カルノシンジペプチダーゼ１を阻害する方法である。好ましくは、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として治療有効量を投与することを含む、カルノシンジペプチダーゼ１を阻害する方法である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものを有効成分として治療有効量を投与することを含む、カルノシンジペプチダーゼ１を阻害する方法である。 Another aspect relating to the method comprises a method of inhibiting carnosine dipeptidase 1, comprising administering to a subject in need of inhibition of carnosine dipeptidase 1 a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient. It is. Preferably, cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucyl glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucyl tyrosine [Cyclo ( Leu-Tyr)], cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucil threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), cycloarginyl isoleucine [ Cyclo (Arg-Ile)], cyclotryptophanyl tyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyl tryptophan (Cyclo (Phe-Trp)), cycloasparaginyl leucine (Cyclo (Asn-Leu)), Cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucil tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)) ), Cyclovalyl lysine (Cyclo (Val-Lys)), Treatment with one or more cyclic dipeptides or salts thereof selected from the group consisting of rotreonylglutamic acid [Cyclo (Thr-Glu)] and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] as an active ingredient A method of inhibiting carnosine dipeptidase 1 comprising administering an effective amount. More preferably, it is a method of inhibiting carnosine dipeptidase 1, which comprises administering a therapeutically effective amount using as an active ingredient a substance containing three or more selected from the above cyclic dipeptides or salts thereof.
　上記方法において、カルノシンジペプチダーゼ１の阻害を必要とする対象とは、本発明のカルノシンジペプチダーゼ１阻害用組成物の前記適用対象と同様である。また、本明細書中において治療有効量とは、本発明のカルノシンジペプチダーゼ１阻害用組成物を上記対象に投与した場合に、投与していない対象と比較して、カルノシンジペプチダーゼ１のカルノシン分解活性が阻害される量のことである。具体的な有効量としては、投与形態、投与方法、使用目的及び対象の年齢、体重、症状等によって適宜設定され一定ではない。 In the above method, the subject requiring inhibition of carnosine dipeptidase 1 is the same as the subject of application of the composition for inhibiting carnosine dipeptidase 1 of the present invention. In the present specification, the therapeutically effective amount refers to the carnosine degradation of carnosine dipeptidase 1 when the composition for inhibiting carnosine dipeptidase 1 of the present invention is administered to the above-mentioned subject as compared to a subject not administered. The amount by which the activity is inhibited. The specific effective amount is appropriately set according to the administration form, administration method, purpose of use and age, weight, symptom, etc. of the subject and is not constant.
　本発明の方法においては、前記治療有効量となるよう、前記特定の環状ジペプチド又はその塩をそのまま、或いは、特定の環状ジペプチド又はその塩を含有する組成物として投与してもよい。 In the method of the present invention, the specific cyclic dipeptide or a salt thereof may be administered as it is or as a composition containing the specific cyclic dipeptide or a salt thereof so that the therapeutically effective amount is obtained.
　本発明の方法によれば、副作用を生じることなくカルノシンジペプチダーゼ１を阻害することが可能になる。 According to the method of the present invention, it is possible to inhibit carnosine dipeptidase 1 without causing side effects.
　以下、本発明を実施例によりさらに詳しく説明するが、これにより本発明の範囲を限定するものではない。当業者は、本発明の方法を種々変更、修飾して使用することが可能であり、これらも本発明の範囲に含まれる。 Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereby. Those skilled in the art can use the method of the present invention with various changes and modifications, and these are also included in the scope of the present invention.
　実施例１．環状ジペプチドによる血清カルノシナーゼ（CNDP1）活性阻害効果の検討
　各種環状ジペプチド標品は、化学合成したものを試験に供した。ヒト血清カルノシナーゼCNDP1は、recombinant Human Carnosine Dipeptidase 1/CNDP1（R＆D systems）を用いた。カルノシンは、東京化成工業社製を用いた。以下の手順で、室温で血清カルノシナーゼ（CNDP1）活性阻害効果を検討した。 Example 1. Examination of the inhibitory effect of serum carnosinase (CNDP1) activity by cyclic dipeptides Various cyclic dipeptide preparations were chemically synthesized and used for the test. Recombinant Human Carnosine Dipeptidase 1 / CNDP1 (R & D systems) was used as human serum carnosinase CNDP1. Carnosine manufactured by Tokyo Chemical Industry Co., Ltd. was used. The serum carnosinase (CNDP1) activity inhibitory effect was examined at room temperature by the following procedure.
　1.5mLエッペンドルフチューブに、バッファー（50mM Tris, pH7.5）に溶解させた2ng/μL CNDP1溶液50μL及び環状ジペプチド溶液25μLを添加し、同じくバッファーに溶解させた4mMカルノシン溶液25μLを添加することで反応を開始した。反応溶液を室温で60分間インキュベートした後、脱イオン水で溶解した1% Trichloroacetic acid (TCA) (Sigma)水溶液50μLを添加し、ボルテックスにて混和することで反応を終結させた。反応終了後のサンプルに、5mg/mL o-Phthaldialdehyde (OPA) (Sigma)含有1.8M水酸化ナトリウム水溶液（10%DMSO含有）を添加し、混和後室温でさらに30分間インキュベートした。バッファーを用いてL-ヒスチジン希釈系列を15.625～250μMの範囲内で作成し、同様にTCAおよびOPAを添加した後、30分間インキュベートしたものを検量線溶液とした。なお、環状ジペプチドの代わりに同含有率のDMSOを含有した水を添加したものをコントロールとした。サンプルおよび検量線溶液全量を96 well black plate に添加し、蛍光光度計を用いて励起波長360nm、蛍光波長460nmにおける蛍光強度を測定した。 To a 1.5 mL Eppendorf tube, add 50 μL of 2 ng / μL CNDP1 solution dissolved in buffer (50 mM Tris, pH 7.5) and 25 μL cyclic dipeptide solution, and then add 25 μL 4 mM carnosine solution dissolved in the same buffer. Started. After incubating the reaction solution at room temperature for 60 minutes, 50 μL of 1% aqueous solution of Trichloroacetic acid (TCA) (Sigma) dissolved in deionized water was added, and the reaction was terminated by vortexing. After completion of the reaction, 5 mg / mL Mo-Phthaldialdehyde (OPA) (Sigma) -containing 1.8 M sodium hydroxide aqueous solution (containing 10% DMSO) was added, and the mixture was further incubated at room temperature for 30 minutes. An L-histidine dilution series using a buffer was prepared in the range of 15.625 to 250 μM, and TCA and OPA were similarly added, followed by incubation for 30 minutes to obtain a calibration curve solution. In addition, what added the water containing DMSO of the same content rate instead of cyclic dipeptide was used as control. The total amount of the sample and the calibration curve solution was added to 96-well black plate, and the fluorescence intensity at an excitation wavelength of 360 nm and a fluorescence wavelength of 460 nm was measured using a fluorometer.
　結果については、酵素（CNDP1）の代わりにバッファーを添加したサンプルにおける蛍光強度を差し引くことで補正値を算出し、コントロールにおける蛍光強度の補正値を100%としたときの各環状ジペプチド含有サンプルにおける蛍光強度の補正値をCNDP1残存活性(%)とした。その結果を表１に示す。 For the results, the correction value was calculated by subtracting the fluorescence intensity in the sample to which the buffer was added instead of the enzyme (CNDP1), and the fluorescence value in each cyclic dipeptide-containing sample when the correction value of the fluorescence intensity in the control was taken as 100%. The intensity correction value was defined as CNDP1 residual activity (%). The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
 　上記の結果から、表１に示した環状ジペプチドはいずれも血清カルノシナーゼ（CNDP1）活性の阻害作用を有することが明らかとなった。
Figure JPOXMLDOC01-appb-T000001
 From the above results, it was revealed that any of the cyclic dipeptides shown in Table 1 has an inhibitory action on serum carnosinase (CNDP1) activity.
　実施例２．直鎖状ジペプチドによる血清カルノシナーゼ（CNDP1）活性阻害効果の検討
　組織カルノシナーゼ（CNDP2）阻害活性が知られている直鎖状ペプチドに関して、血清カルノシナーゼ（CNDP1）活性阻害効果を検討した。各種直鎖状ジペプチド標品は、BACHEM社より購入したものを試験に供した。その他の材料は実施例１と同一のものを用い、実施例１と同様の方法で直鎖状ジペプチドによる血清カルノシナーゼ（CNDP1）活性の阻害作用を調べた。その結果を表２に示す。 Example 2 Examination of Serum Carnosinase (CNDP1) Activity Inhibitory Effect by Linear Dipeptide For linear peptides known to have tissue carnosinase (CNDP2) inhibitory activity, the serum carnosinase (CNDP1) activity inhibitory effect was examined. Various linear dipeptide preparations purchased from BACHEM were used for the test. The other materials were the same as in Example 1, and the inhibitory action of serum carnosinase (CNDP1) activity by the linear dipeptide was examined in the same manner as in Example 1. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
 　表２に示される通り、CNDP2阻害活性が知られている直鎖状ジペプチドは濃度を５００μＭとした場合であっても血清カルノシナーゼ（CNDP1）活性の阻害効果は見られなかった。この結果から、CNDP2阻害活性が知られている直鎖状ジペプチドは血清カルノシナーゼ（CNDP1）活性の阻害作用を有していないことが明らかとなった。また、上記の結果から、表１に示された環状ジペプチドはCNDP2阻害活性が知られている直鎖状ジペプチドとは異なる構造に基づいて血清カルノシナーゼ（CNDP1）の活性を阻害すること、そしてCNDP1の阻害物質と組織カルノシナーゼ（CNDP2）の阻害物質とは互いに異なり関連性を持たないことが示唆された。
Figure JPOXMLDOC01-appb-T000002
 As shown in Table 2, the linear dipeptide known for CNDP2 inhibitory activity did not show an inhibitory effect on serum carnosinase (CNDP1) activity even when the concentration was 500 μM. From these results, it was revealed that linear dipeptides known to have CNDP2 inhibitory activity have no inhibitory action on serum carnosinase (CNDP1) activity. Moreover, from the above results, the cyclic dipeptide shown in Table 1 inhibits the activity of serum carnosinase (CNDP1) based on a structure different from that of the linear dipeptide known to have CNDP2 inhibitory activity. It was suggested that the inhibitor and the inhibitor of tissue carnosinase (CNDP2) are different from each other and have no relation.
　本発明は、特定の環状ジペプチド又はその塩を有効成分として含有するカルノシンジペプチダーゼ１阻害用組成物を提供するものである。本発明は、認知機能低下等の予防又は改善に資する新たな手段を提供するものであるため、産業上の利用性が高い。 The present invention provides a composition for inhibiting carnosine dipeptidase 1 containing a specific cyclic dipeptide or a salt thereof as an active ingredient. Since the present invention provides a new means that contributes to prevention or improvement of cognitive function decline or the like, the industrial applicability is high.

Claims (10)

  1. 　アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として含有するカルノシンジペプチダーゼ１阻害用組成物であって、
    　前記環状ジペプチド又はその塩が、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記カルノシンジペプチダーゼ１阻害用組成物。     A composition for inhibiting carnosine dipeptidase 1 containing, as an active ingredient, a cyclic dipeptide having an amino acid as a structural unit or a salt thereof,
    The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine. Siltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucine threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloarginylisoleucine (Cyclo (Arg-Ile)), cyclotryptophanyltyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cycloasparaginylleucine (Cyclo (Asn -Leu)], cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)], Cyclovalyllici Including one or more selected from the group consisting of [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] The above-mentioned composition for inhibiting carnosine dipeptidase 1
  2. 　認知機能低下、糖尿病、免疫機能低下、血管若しくは組織の炎症、酸化ストレス若しくは終末糖化産物の産生に起因する各種疾患、アルツハイマー、又は自閉症の予防又は改善用である、請求項１に記載のカルノシンジペプチダーゼ１阻害用組成物。 It is for prevention or improvement of various diseases, Alzheimer, or autism caused by cognitive decline, diabetes, immune function decline, vascular or tissue inflammation, oxidative stress or advanced glycation end products. A composition for carnosine dipeptidase 1 inhibition.
  3. 　環状ジペプチド又はその塩が、動植物由来ペプチドから得られるものである、請求項１又は２に記載のカルノシンジペプチダーゼ１阻害用組成物。 The composition for carnosine dipeptidase 1 inhibition according to claim 1 or 2, wherein the cyclic dipeptide or a salt thereof is obtained from an animal or plant-derived peptide.
  4. 　環状ジペプチド又はその塩の含有量が２００μｇ／１００ｇ／Ｂｘ以上である、請求項１～３のいずれか１項に記載のカルノシンジペプチダーゼ１阻害用組成物。 The composition for inhibiting carnosine dipeptidase 1 according to any one of claims 1 to 3, wherein the content of the cyclic dipeptide or a salt thereof is 200 µg / 100 g / Bx or more.
  5. 　環状ジペプチド又はその塩の含有量が１０００μｇ／１００ｇ／Ｂｘ以上である、請求項１～３のいずれか１項に記載のカルノシンジペプチダーゼ１阻害用組成物。 The composition for inhibiting carnosine dipeptidase 1 according to any one of claims 1 to 3, wherein the content of the cyclic dipeptide or a salt thereof is 1000 µg / 100 g / Bx or more.
  6. 　カルノシンジペプチダーゼ１阻害により発揮される機能の表示を付した、請求項１～５のいずれか１項に記載のカルノシンジペプチダーゼ１阻害用組成物。 6. The composition for inhibiting carnosine dipeptidase 1 according to any one of claims 1 to 5, which is labeled with a function exhibited by carnosine dipeptidase 1 inhibition.
  7. 　機能の表示が、「認知機能の低下を抑制する」、「認知機能の維持を期待する」、「血糖値の上昇を抑制する」、「免疫機能を高める」、「抗酸化作用を期待する」、「酸化ストレスを低減する」、「抗糖化作用を期待する」、「糖化ストレスを低減する」、「血管の炎症を抑制する」、「アルツハイマー症の予防若しくは改善を期待する」、及び「自閉症の予防若しくは改善を期待する」からなる群から選択されるものである、請求項６に記載の組成物。 Function indications “suppress cognitive function decline”, “expect cognitive function maintenance”, “suppress blood sugar level rise”, “enhance immune function”, “antioxidant effect” , “Reduce oxidative stress”, “Expect anti-glycation effect”, “Reduce glycation stress”, “Inhibit vascular inflammation”, “Expect prevention or improvement of Alzheimer's disease”, The composition according to claim 6, which is selected from the group consisting of “expecting prevention or improvement of autism”.
  8. 　前記組成物が剤である、請求項１～７のいずれか１項に記載のカルノシンジペプチダーゼ１阻害用組成物。 The composition for inhibiting carnosine dipeptidase 1 according to any one of claims 1 to 7, wherein the composition is an agent.
  9. 　カルノシンジペプチダーゼ１を阻害するための、アミノ酸を構成単位とする環状ジペプチド又はその塩の使用であって、
    　前記環状ジペプチド又はその塩が、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記使用。     Use of a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for inhibiting carnosine dipeptidase 1,
    The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine. Siltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucine threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloarginylisoleucine (Cyclo (Arg-Ile)), cyclotryptophanyltyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cycloasparaginylleucine (Cyclo (Asn -Leu)], cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)], Cyclovalyllici Including one or more selected from the group consisting of [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] The use as described above.
  10. 　アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として使用する、カルノシンジペプチダーゼ１を阻害する方法であって、
    　前記環状ジペプチド又はその塩が、シクロリシルリシン〔Cyclo(Lys-Lys)〕、シクロイソロイシルグルタミン酸〔Cyclo(Ile-Glu)〕、シクロイソロイシルリシン〔Cyclo(Ile-Lys)〕、シクロロイシルチロシン〔Cyclo(Leu-Tyr)〕、シクロメチオニルバリン〔Cyclo(Met-Val)〕、シクロイソロイシルトレオニン〔Cyclo(Ile-Thr)〕、シクログルタミルロイシン〔Cyclo(Glu-Leu)〕、シクロアルギニルイソロイシン〔Cyclo(Arg-Ile)〕、シクロトリプトファニルチロシン〔Cyclo(Trp-Tyr)〕、シクロフェニルアラニルトリプトファン〔Cyclo(Phe-Trp)〕、シクロアスパラギニルロイシン〔Cyclo(Asn-Leu)〕、シクロメチオニルイソロイシン〔Cyclo(Met-Ile)〕、シクロイソロイシルチロシン〔Cyclo(Ile-Tyr)〕、シクロメチオニルセリン〔Cyclo(Met-Ser)〕、シクロバリルトレオニン〔Cyclo(Val-Thr)〕、シクロバリルリシン〔Cyclo(Val-Lys)〕、シクロトレオニルグルタミン酸〔Cyclo(Thr-Glu)〕、及びシクロチロシルチロシン〔Cyclo(Tyr-Tyr)〕からなる群から選択される１つ又は２つ以上を含むものである、前記方法。     A method for inhibiting carnosine dipeptidase 1, which uses a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
    The cyclic dipeptide or a salt thereof may be cyclolysyl lysine [Cyclo (Lys-Lys)], cycloisoleucil glutamic acid [Cyclo (Ile-Glu)], cycloisoleucil lysine [Cyclo (Ile-Lys)], cycloleucine. Siltyrosine (Cyclo (Leu-Tyr)), cyclomethionyl valine (Cyclo (Met-Val)), cycloisoleucine threonine (Cyclo (Ile-Thr)), cycloglutamyl leucine (Cyclo (Glu-Leu)), Cycloarginylisoleucine (Cyclo (Arg-Ile)), cyclotryptophanyltyrosine (Cyclo (Trp-Tyr)), cyclophenylalanyltryptophan (Cyclo (Phe-Trp)), cycloasparaginylleucine (Cyclo (Asn -Leu)], cyclomethionylisoleucine (Cyclo (Met-Ile)), cycloisoleucine tyrosine (Cyclo (Ile-Tyr)), cyclomethionylserine (Cyclo (Met-Ser)), cyclovalylthreonine (Cyclo (Val-Thr)], Cyclovalyllici Including one or more selected from the group consisting of [Cyclo (Val-Lys)], cyclothreonyl glutamic acid [Cyclo (Thr-Glu)], and cyclotyrosyltyrosine [Cyclo (Tyr-Tyr)] The method as described above.
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