TW201717952A - Composition that contains ring-shaped dipeptide and inhibits serum carnosinase - Google Patents

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

Serum carnitine-degrading enzyme blocking composition containing cyclic dipeptide

The present invention relates to a serum carnitine-degrading enzyme inhibitory composition. More specifically, the present invention relates to a carnitine dipeptidase 1 inhibitory composition containing a specific cyclic dipeptide as an active ingredient or a salt thereof, and a specific cyclic dipeptide or a salt thereof for use in carnitine dipeptidase 1. Use, a method of blocking carnitine dipeptidase 1, and a composition containing a specific cyclic dipeptide or a salt thereof and carnitine.

Carnitine is a dipeptide composed of β -alanine and histidine, which is present in muscle or nerve tissue at a high concentration in mammals such as humans. As a carnitine, (1) proton buffer activity, (2) calcium secretion and calcium sensitivity control, (3) antioxidant action, (4) metal ion chelation, (5) histidine/tissue are known. Extracellular donor of amine, (6) improvement of hyperglycemia, (7) anti-inflammatory effect, and the like. In addition, for the action of carnitine, inhibition of the formation of the final glycation product or inhibition of cell death caused by cerebral ischemia, accumulation of amyloid β in Alzheimer's disease (AD) model mice, immunization Regulations have also been reported. Since carnitine imparts various functions to the body, it is decomposed by carnitine-decomposing enzymes to become a subject of the pharmacological action.

It is known that there are two types of carnosine dipeptidase 1 (CNDP1) and carnosine dipeptidase 2 (CNDP2) in carnitine-degrading enzyme. Among them, CNDP1 exists only in higher primates (humans and large monkeys), and almost no other mammals exist (Non-Patent Document 1). These CNDP1 and CNDP2 are proteins that are highly homologous to each other, and their tissue distribution or enzyme characteristics are different, and each has a different function.

Regarding CNDP2, for example, Bestatin is known as the inhibitor (Non-Patent Document 2), and other such as β -alanine, and Gly-L-His and L-Pro-L-His are linear. The inhibition of the peptide against CNDP2 has been reported (Patent Document 1). On the other hand, CNDP1 has, for example, a report that phenanthroline is used as the inhibitor (Non-Patent Document 3), but focuses on the inhibition of the activity of CNDP1, and it has not been clearly known as a carnitine decomposition inhibitor.

As described above, CNDP1 and CNDP2 are proteins different from each other, and therefore the inhibitors for each enzyme are also different. Actually, the above-mentioned CNDP2 inhibitor, Bestatin, has no effect on the inhibition of CNDP1 (Non-Patent Document 4). Further, it is known that the above-described phenanthroline has an inhibitory activity against CNDP1 and exhibits oral toxicity as the side effect. Therefore, if a safer inhibitor of CNDP1 can be found, it can be applied to the clinical situation of a disease or symptom associated with the activity of CNDP1.

Regarding CNDP1, as described in Non-Patent Document 5, an animal whose gene is introduced into human serum carnosine (CNDP1) in db/db mice The model, which shows a high value of fasting blood glucose and HbA1c in the younger period, exhibits diabetes-like symptoms such as weight loss. That is, it has been revealed that carnitine decomposition by serum carnosine (CNDP1) may become a cause of disease. Therefore, serum carnitine breakdown enzyme (CNDP1) hinders the use of the composition to efficiently reach L-carnitine to plasma, target organs or other organs, and can be used as various causes of diabetes or oxidative stress and the production of terminal glycation products. The preventive effect of the disease can be improved.

Further, with respect to a plurality of documents such as Non-Patent Document 6, there has been reported a correlation between a specific gene polymorphism ((CTG)n) in the serum carnosinase (CNDP1) gene and the onset of diabetic renal disorder. In this regard, in Non-Patent Document 7, the risk of developing a diabetic nephropathy in a homozygous (CTG) 5 holder is low, and the serum myopeptidase activity is also low. Therefore, inhibition of serum carnosinase activity is important for the maintenance of carnitine concentration, and it is considered to be effective for prevention or treatment of related diseases.

In addition, as a test example of the in vivo dynamic test after oral intake of carnitine in humans, Non-Patent Document 8 is mentioned. According to this document, the individual difference in carnitine blood concentration at each time after ingestion of carnitine 60 mg/kg is large, and is also present in subjects who have not significantly increased carnitine concentration in blood compared with before ingestion. (17 out of 25), in comparison with the group that was identified as having risen, it was found that the activity or protein amount of serum carnosin was significantly low. From this, it can be seen that when the action of serum carnosinase (CNDP1) is inhibited, the blood carnitine concentration can be effectively maintained.

So CNDP1 is for being a mammal, especially for Since there are various effects in the human body, it is strongly expected that the drug having high safety when the activity is inhibited is strongly expected.

[Advanced technical literature] [Patent Literature]

[Patent Document 1] International Publication WO2004/064866

[Non-patent literature]

[Non-Patent Document 1] Clin. Chim. Acta, 1991, 196, 193-205.

[Non-Patent Document 2] Biol. Chem. Hoppe Seyler, 1988, 369, 1281-1286.

[Non-Patent Document 3] Molecules, 2014, 19, 2299-2329

[Non-Patent Document 4] Clin. Chim. Acta 1982, 123, 221-231.

[Non-Patent Document 5] Diabetes, 2007, 56, 2425-2432. Epub 2007 Jun 29.

[Non-Patent Document 6] Diabetes, 2007, 56, 2410-2413.

[Non-Patent Document 7] Diabetes, 2005, 54, 2320-2327.

[Non-Patent Document 8] Am. J. Physiol. Renal. Physiol., 2012, 302(12), F1537-F1544.

An object of the present invention is to provide a composition for inhibiting serum carnitine-degrading enzyme (CNDP1) which has high biosafety and maintains blood concentration in carnitine. Further, an object of the present invention is to provide a composition for inhibiting CNDP1, a method for inhibiting CNDP1, and a composition having high biosafety and capable of maintaining a concentration of blood in carnitine.

The inventors of the present invention conducted detailed review of the above problems and focused on the use of cyclic dipeptides. The cyclic dipeptide is a dipeptide having a cyclic structure formed by dehydration condensation of an amine group and a carboxyl group which are present at the terminal of a linear dipeptide, and various physiological activities have been attracting attention in recent years. The present inventors also conducted a detailed review of a majority of about 200 kinds of cyclic dipeptides formed by a combination of natural amino acids, from which it was found that a specific cyclic dipeptide has an inhibitory activity of CNDP1. Based on this finding, the inventors completed the present invention.

That is, the present invention relates to the following, but is not limited thereto.

(1) A carnitine dipeptidase 1 inhibitory composition which is a carnitine dipeptidase 1 inhibitory composition containing a cyclic dipeptide which is a constituent unit of an amino acid as an active ingredient or a salt thereof, wherein The cyclic dipeptide or a salt thereof is selected from the group consisting of Cyclo(Lys-Lys), Cyclo(Ile-Glu), and hetero ring Cyclo(Ile-Lys), cyclo-leucine, Cyclo(Leu-Tyr), cyclomethenamide-proline lysine [Cyclo(Met-) Val)], Cyclo(Ile-Thr), Cyclo(Glu-Leu), Cyclosylamine-Isoleucine (Arg-Ile)], cyclosamine thioglycolic acid [Cyclo(Trp-Tyr)], cyclophenylalanine phthalic acid [Cyclo(Phe-Trp)], cycloaspartic acid leucine [Cyclo(Asn-Leu)], cyclomethionine, Cyclo(Met-Ile), cycloisoleucine, Cyclo(Ile-Tyr), cyclomethine Cyclo(Met-Ser), Cyclo(Val-Thr), Cyclo(Val-Lys), Cyclosulphate One or two or more of a group consisting of Cyclo (Thr-Glu) and Cyclo (Tyr-Tyr).

(2) Prevention or improvement of various diseases caused by decreased cognitive function, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or the production of terminal glycation products, Alzheimer's disease or autism (1) The carnitine dipeptidase 1 inhibitory composition described.

(3) The cyclic dipeptide or a salt thereof is a carnitine dipeptidase 1 inhibitory composition described in (1) or (2), which is obtained from a peptide derived from an automatic plant.

(4) The carnitine dipeptidase 1 inhibitory composition according to any one of (1) to (3), wherein the content of the cyclic dipeptide or the salt thereof is 200 μg/100 g/Bx or more.

(5) The carnitine dipeptidase 1 inhibitory composition according to any one of (1) to (3), wherein the content of the cyclic dipeptide or the salt thereof is 1000 μg/100 g/Bx or more.

(6) A functional representation expressed by carnitine dipeptidase 1 The carnitine dipeptidase 1 inhibitory composition according to any one of (1) to (5).

(7) The function is expressed as follows: "Reducing cognitive function reduction", "Expecting cognitive function maintenance", "Suppressing blood sugar level increase", "Improving immune function", "Expecting anti-oxidation effect", "Reducing oxidative stress" "Awaiting anti-glycation", "reducing glycemic pressure", "inflaming blood vessels", "expecting prevention or improvement of Alzheimer's disease" and "expecting prevention or improvement of autism" The composition described in (6).

(8) The carnitine dipeptidase 1 inhibitory composition according to any one of (1) to (7).

(9) Use of a cyclic dipeptide or a salt thereof having an amino acid as a constituent unit when carnitine dipeptidase 1 is used, wherein the cyclic dipeptide or a salt thereof is selected from the group consisting of lysine-based lysine Acid [Cyclo(Lys-Lys)], cycloisoleucine glutamic acid [Cyclo (Ile-Glu)], cycloisoleucine lysine lysine [Cyclo (Ile-Lys)], cycloleucine Cyclo(Leu-Tyr), cyclomethicin, Cyclo(Met-Val), cycloheximyl sulphate, Cyclo(Ile-Thr), ring Cyclo(Glu-Leu), cyclosamine, Cyclo(Arg-Ile), Cyclo(Trp-Tyr) , Cyclo(Phe-Trp), Cyclo(Asn-Leu), cyclomethicone-based isoleucine [Cyclo(Met) -Ile)], cycloisoleucine tyrosine acid [Cyclo (Ile-Tyr)], cyclomethicin thiol serine [Cyclo(Met-Ser)], Cyclo(Val-Thr), Cyclo(Val-Lys), Cyclosulphonyl glutamine One or two or more of a group of acid [Cyclo (Thr-Glu)] and cyclo tyrosine tyrosine (Cyclo (Tyr-Tyr)].

(10) A method for inhibiting carnitine dipeptidase 1 using an amino acid as a constituent unit of a cyclic dipeptide or a salt thereof as an active ingredient, wherein the cyclic dipeptide or a salt thereof is selected from the group consisting of a cyclic lysine group Cyclo(Lys-Lys), cycloheximide glutamic acid [Cyclo(Ile-Glu)], cycloisoleucine lysine (Cyclo(Ile-Lys)], ring Cyclo(Leu-Tyr), cyclomethicin, Cyclo(Met-Val), Cyclo(Ile-Thr) 】, cycloglutamine leucine, Cyclo(Glu-Leu), cyclosamine, Cyclo(Arg-Ile), cycloamine thiol tyrosine [Cyclo(Trp-) Tyr)], Cyclo(Phe-Trp), Cyclo(Asn-Leu), Cyclomethalin-isoleucine Cyclo(Met-Ile)], Cyclo(Ile-Tyr), cyclomethicone, Cyclo(Met-Ser), cyclomethamine Amine acid [Cyclo(Val-Thr)], cyclodecyl lysine lysine [Cyclo (Val-Lys)], cyclosulphonyl glutamic acid [Cyclo (Thr-Glu)] And the ring acyl tyrosine tyramine [Cyclo (Tyr-Tyr)] are groups of one or two or more persons.

According to the present invention, a composition having an excellent serum carnitine breakdown enzyme (CNDP1) inhibitory effect can be provided. According to the composition of the present invention, since the carnitine decomposition delay effect by the function inhibition of CNDP1 can be obtained, a higher concentration of carnitine can be efficiently delivered to plasma, a target organ or other organs. Therefore, the composition of the present invention has been previously known to have various pharmacological effects on carnitine (reduced cognitive function caused by schizophrenia, diabetes, decreased immune function, inflammation of blood vessels or tissues, and oxidative stress). The improvement of various diseases, Alzheimer's disease, prevention of autism, and improvement effect is effective.

The cyclic dipeptide or a salt thereof contained as an active ingredient in the composition of the present invention is also contained in a heat-treated product of a peptide derived from a food protein, and therefore has high safety and has few side effects compared with conventional pharmaceuticals. Further, the cyclic dipeptide has excellent lipophilicity as compared with the linear dipeptide, and is sufficient for high-concentration filling of the oily substrate. Therefore, the composition of the present invention can have excellent usability in formulation. Further, since the cyclic dipeptide is rich in fat solubility and is not only a dipeptide composed of peptide bonds alone, it is resistant to the action of various peptide-decomposing enzymes secreted in the digestive tract, and therefore high digestive tract absorbability is also expected.

[Formation of the Invention] 1. Carnitine dipeptidase 1 and carnitine dipeptidase 1 block

In this specification called "dipeptidase carnitine 1" represents carnitine (L- carnitine) may be decomposed into β - alanine and histidine carnitine serum enzymes decompose. Carnitine dipeptidase (carnitine breakdown enzyme) is abbreviated as CNDP (carnosine dipeptidase), also known as carnosine or botulinum. The carnitine dipeptidase contains CNDP1 of serum (type) carnitine breakdown enzyme and CNDP2 of tissue (type) carnitine breakdown enzyme. Among these, the carnitine dipeptidase to be used in the present invention is CNDP1, which is distinguishable from CNDP2.

The "carnitine dipeptidase 1 inhibition" in the present specification is a carnitine decomposition activity which inhibits carnitine dipeptidase 1. The inhibition of carnitine dipeptidase 1 can be evaluated according to known methods. For example, when carnitine is contacted with carnitine dipeptidase 1, histidine is produced in carnitine. At this time, the fluorescence of histidine is determined by the presence of histidine, so the fluorescence intensity is determined. A reduced investigation can assess the inhibitory effect of carnitine dipeptidase 1.

2. Cyclic dipeptide

The term "cyclic dipeptide" as used in the present specification means a compound having an amino acid as a constituent unit and having a diketopiperazine structure formed by dehydration condensation of an amine group and a carboxyl group of an amino acid. Dipeptides. Therefore, a cyclic dipeptide can be distinguished from a chain dipeptide. Further, in the present specification, a cyclic dipeptide or a salt thereof is generally referred to as a cyclic dipeptide. In the present specification, if the amino acid of the cyclic dipeptide is identical, the order of precedence of these sequences is not important, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)] are represented. The same cyclic dipeptide.

The cyclic dipeptide mediates the indole bond and the end of the two amino acids The terminal moiety is bonded (ie, the cyclic dipeptide has a cyclic structure formed by a amide bond between an amine terminal and a carboxy terminal), and a linear chain of a carboxyl group or an amine group which exposes a polar group at a terminal portion of the molecule The dipeptide (particularly a linear dipeptide composed of the same amino acid) has a characteristic that the cyclic dipeptide has high fat solubility. Therefore, the cyclic dipeptide has excellent digestive tract permeability or membrane permeability as compared with the linear dipeptide. This can also be seen from the results of a test for the permeation of a compound using a rat that has been reported in the past to reverse the intestinal tract (J. Pharmacol, 1998, 50: 167-172). Further, the cyclic dipeptide is also improved in resistance to various peptidases by the specific structure.

The cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention is selected from the group consisting of Cyclo(Lys-Lys), cycloisoleucine-based glutamic acid [Cyclo(Ile) -Glu)], cyclohexyl lysine lysine [Cyclo(Ile-Lys)], cycloleucine tyrosine acid [Cyclo (Leu-Tyr)], cyclomethalin-decyl glutamate [ Cyclo(Met-Val)], cyclohexyl sulphate [Cyclo(Ile-Thr)], cycloglutamine leucine (Cyclo(Glu-Leu)], cyclospermine thiol Amine acid [Cyclo(Arg-Ile)], cyclosamine thioglycolic acid [Cyclo(Trp-Tyr)], cyclophenylalanine phthalic acid [Cyclo(Phe-Trp)], cycloaspartamide Cyclo(Asn-Leu), cyclomethicone, Cyclo(Met-Ile), cyclomethicone, Cyclo(Ile-Tyr), Cyclo(Met-Ser), Cyclo(Val-Thr), Cyclo(Val-Lys) 〕, Cyclosulphonyl glutamate [Cyclo (Thr- One or two or more of Glu)] and Cyclo(tyr-Tyr). The number of the cyclic dipeptides or the salts thereof is not particularly limited, and in the present invention, it is preferred to have three or more selected from the above cyclic dipeptides or salts thereof as an active ingredient. Further, the cyclic dipeptide or a salt thereof is selected from the group consisting of Cyclo(Trp-Tyr) and Cyclo(Ile-Lys). , Cyclo(Phe-Trp), Cyclo(Ile-Thr), Cyclomethamine Cyclosylamine [Cyclo(Met-) Ser)], cyclomethamine decyl glutamic acid [Cyclo(Met-Val)], cyclosamine decyl isoleucine [Cyclo(Arg-Ile)], cycloglutamine leucine leucine (Glu-Leu)] and one or more of the group of cyclo sulphonyl glutamate (Cyclo (Thr-Glu)) are preferably selected from the group consisting of cyclosamine decyl tyrosine [ Cyclo(Trp-Tyr)], cyclohexyl lysine lysine [Cyclo(Ile-Lys)], cyclophenylalanine phthalic acid [Cyclo(Phe-Trp)], and cycloisoleucine One or two or more of the group consisting of Cyclo (Ile-Thr) are preferred.

In the present specification, the "salt of a cyclic dipeptide" means any salt (including an inorganic salt and an organic salt) which is pharmacologically acceptable as the cyclic dipeptide, and examples thereof include a sodium salt of the cyclic dipeptide. Potassium, calcium, magnesium, ammonium, hydrochloride, sulfate, nitrate, citrate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactic acid) Salt, succinate, fumarate, propionate, formate, benzoate, picrate, besylate, trifluoroacetate, etc., but not Limited to this. The salt of the cyclic dipeptide can be readily prepared by a manufacturer according to any method known in the art.

The cyclic dipeptides used in the present invention can be prepared according to methods well known in the art. For example, it can be produced by a chemical synthesis method, an enzyme method, or a microbial fermentation method, or can be synthesized by dehydrating and cyclizing a linear peptide, and can be synthesized according to JP-A-2003-252896 or Journal of Peptide Science, 10,737. The method described in -737, 2004 is modulated. For example, a peptide obtained by administering an enzyme treatment or heat treatment to a raw material containing an automatic plant protein, and further applying a high-temperature heat treatment, can obtain a peptide heat-treated product of an autonomic plant rich in a cyclic dipeptide. From the above, it can be understood that the cyclic dipeptide or a salt thereof used in the present invention may be obtained by chemical or biosynthesis, or may be derived from a peptide of an automated plant.

3. Come to the automatic plant peptide

The "peptide for automatic plant" in the present specification is not particularly limited, and for example, soybean peptide, tea peptide, malt peptide, lactopeptide, placental peptide, collagen peptide or the like can be used. Commercially available products can also be used by preparing an automatic plant peptide from a protein of an automatic plant or a protein-containing raw material.

3-1. Soy peptide

In the present specification, the "soybean peptide" means a low molecular peptide obtained by subjecting a soybean protein to an enzyme treatment or heat treatment by lowering a protein. As a raw material, soybean (scientific name: Glycine max) may be It is used in a limited variety such as a variety or a production place, and it is also possible to use a processed product such as a pulverized product.

3-2. Tea peptide

In the present specification, the "tea peptide" is a low molecular peptide derived from tea which is subjected to an enzyme treatment or heat treatment for a tea (containing a tea leaf or a tea shell) extract by subjecting the protein to a low molecular weight. As the tea leaves to be extracted, tea leaves, stems, and the like, which are produced by tea tree (scientific name: Camellia sinensis), can be extracted and used as a drinkable portion. Further, the form may be a large leaf, a powder, or the like, and is not limited. For the harvest period of tea, it can also be selected according to the desired flavor.

3-3. Malt peptide

The "malt peptide" referred to in the present specification is a low molecular peptide derived from malt obtained by subjecting malt or an extract obtained from the pulverized material to an enzyme treatment or heat treatment to lower the molecular weight of the protein. The malt peptide as a raw material can be used without restrictions such as variety or origin, but it is particularly suitable for barley malt which has been germinated by the seeds of barley. Moreover, for the present specification, barley malt is sometimes labeled only with malt.

3-4. Milk peptide

The term "milk peptide" as used in the present specification means a molecule in which milk protein of a component derived from milk is decomposed into at least a plurality of bonded amino acids. More specifically, milk protein such as whey (whey protein) or casein can be cited. The enzyme such as protease is hydrolyzed, and the filtrate obtained by the filtration is sterilized and/or concentrated, and then the obtained whey peptide, casein peptide or the like is dried.

3-5. Placental peptide

The placenta, which is a mammalian placenta, can be used as a health food, cosmetics, and pharmaceutical material in recent years due to its excellent functionality. The "placental peptide" referred to in the present specification is a method in which the placenta is subjected to enzyme treatment or subcritical treatment to become solubilized and low molecular weight. Further, although different from the original meaning, the extract obtained from the placenta of the plant has the same physiological effect as the placenta from the placenta, and can be used for health foods, cosmetics, and the like, each of which is called a plant placenta. In the "placental peptide" in the present specification, the plant placenta may be subjected to enzyme treatment or subcritical treatment, and may also contain solubilized or low molecular weight.

3-6. Collagen peptide

In the present specification, the term "collagen peptide" means a low molecular peptide obtained by subjecting collagen or a pulverized material thereof to an enzyme treatment or heat treatment to lower the collagen. Collagen is the main protein of the connective tissue of animals, and contains the largest amount of protein in human mammalian bodies.

4. Automatic peptide heat treatment of plants

As described above, in the future, after the peptide of the automatic plant is subjected to high-temperature heat treatment, a peptide heat-treated product of the autonomic plant rich in the cyclic dipeptide can be obtained. The term "high-temperature heat treatment" as used herein means that the treatment is carried out for a certain period of time at a temperature of 100 ° C or higher and a pressure exceeding atmospheric pressure. As high temperature A high-pressure treatment device, a pressure-resistant extraction device, a pressure cooker, a high-pressure autoclave, or the like can be used in accordance with conditions.

The temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, and is preferably 100 ° C to 170 ° C, preferably 110 ° C to 150 ° C, more preferably 120 ° C to 140 ° C. In the case where the pressure-resistant extraction device is used as the heating device, the outlet temperature value of the extraction column is measured, and when the high-pressure autoclave is used as the heating device, the temperature value of the center temperature in the pressure vessel is measured.

The pressure in the high-temperature heat treatment is not particularly limited as long as it exceeds the atmospheric pressure, and is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, still more preferably 0.101 MPa to 0.48 MPa.

The high-temperature heat treatment time is not particularly limited as long as it can obtain a treatment containing a cyclic dipeptide, and is preferably from 15 minutes to 600 minutes, preferably from 30 minutes to 500 minutes, more preferably from 60 minutes to 300 minutes. Degree of division.

In addition, the high-temperature heat treatment conditions of the peptide of the automatic plant are not particularly limited as long as the treatment product containing the cyclic dipeptide is obtained, and [temperature: pressure: time] is [100 ° C to 170 ° C: 0.101 MPa to 0.79). MPa: 15 minutes to 600 minutes is preferred, preferably [110 ° C ~ 150 ° C: 0.101 MPa ~ 0.60 MPa: 30 minutes to 500 minutes], more preferably [120 ° C ~ 140 ° C: 0.101 MPa ~ 0.48 MPa: 60 minutes to 300 points].

And, for the resulting peptide heat treatment of automatic plants The product may be subjected to filtration, centrifugation, concentration, ultimate filtration, freeze drying, powdering, etc. as needed. In addition, when the specific cyclic dipeptide in the peptide heat-treated product of the automatic plant does not have a desired content, other peptides, commercial products, and synthetic products of the automatic plant can be appropriately added to the specific cyclic dipeptide which is insufficient. .

5. Carnitine dipeptidase 1 inhibitory composition 5-1. Carnitine dipeptidase 1 hindered composition containing a cyclic dipeptide

One aspect of the present invention is a carnitine dipeptidase 1 inhibitory composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient.

The carnitine dipeptidase 1 hindrance composition of the present invention contains a compound selected from the group consisting of Cyclo(Lys-Lys), Cyclo(Ile-Glu), and Cyclo(Ile-Glu). 】, Cyclo(Ile-Lys), Cyclo (Leu-Tyr), Cyclomethamine Cyclosamine (Cyclo(Met) -Val)], Cyclo(Ile-Thr), Cyclo(Glu-Leu), Cyclosamine-Isoleucine Cyclo(Arg-Ile)], cyclosamine tyrosine acid [Cyclo(Trp-Tyr)], cyclophenylalanine phthalic acid [Cyclo(Phe-Trp)], cyclo-aspartame leucine Acid [Cyclo(Asn-Leu)], cyclomethionine, Cyclo(Met-Ile), cycloisoleucine, Cyclo(Ile-Tyr), cyclomethicone Cyclo(Met-Ser), Cyclo(Val-Thr), Cyclo(Val-Lys), ring Su One or two or more cyclic dipeptides or a salt thereof in the group consisting of Cyclo(Thr-Glu) and Cyclo(Tyr-Tyr) Active ingredient. The number of the cyclic dipeptide or the salt thereof contained in the composition for inhibiting carnitine dipeptidase 1 of the present invention is not particularly limited, and in the present invention, three monomers selected from the above cyclic dipeptide or a salt thereof are contained. The above is better. The cyclic dipeptide or a salt thereof is selected from the group consisting of Cyclo(Trp-Tyr), Cyclo(Ile-Lys), and a ring. Phenylaminotryptophanic acid [Cyclo(Phe-Trp)], cycloisoleucine, Cyclo(Ile-Thr), cyclomethicone, Cyclo(Met-Ser) 】, cyclomethine decyl glutamic acid [Cyclo (Met-Val)], cyclosamine thiol isoleucine [Cyclo (Arg-Ile)], cycloglutamine leucine (Cyclol) One or two or more of -Leu)] and cyclosulphonyl glutamic acid [Cyclo(Thr-Glu)] are preferably selected from the group consisting of cyclosamine thioglycolic acid [Cyclo(Trp-) Tyr)], cyclohexyl lysine lysine [Cyclo(Ile-Lys)], cyclophenylalanine phthalic acid [Cyclo(Phe-Trp)], and cycloisoleucine guanidinosine [ One or two or more of the groups of Cyclo (Ile-Thr) are preferred.

The content of the cyclic dipeptide or the salt thereof in the composition for the carnitine dipeptidase 1 of the present invention may be an amount in which the desired effect of the present invention can be obtained in consideration of the administration form, the administration method, and the like. There is no particular limitation. For example, when soybean peptide, tea peptide, malt peptide, lactopeptide, placental peptide, or collagen peptide is used as a raw material, it is used as a cyclic lysine-based lysine in the composition of the carnitine dipeptidase 1 barrier of the present invention. [Cyclo (Lys-Lys)], ring bright Amine glutamic acid [Cyclo(Ile-Glu)], cycloisolysyl lysine lysine [Cyclo (Ile-Lys)], cyclo leucine tyrosine acid [Cyclo (Leu-Tyr)], Cyclomethate, Cyclo(Met-Val), Cyclo(Ile-Thr), Cyclo(Glu-Leu) )], cyclosamine decyl isoleucine [Cyclo(Arg-Ile)], cyclotryptamine thioglycolic acid [Cyclo(Trp-Tyr)], cyclophenylalanine phthalic acid [Cyclo (Phe) -Trp)], Cyclo(Asn-Leu), cyclomethicone, Cyclo(Met-Ile), cycloisoleucine-mercaptotyramine Acid [Cyclo(Ile-Tyr)], cyclomethicin-based thioglycolic acid [Cyclo(Met-Ser)], cyclodecylamine-threonine (Cyclo-Val), cyclodecylamine Lysine (Cyclo-Val), Cyclo(Thr-Glu), Cyclo(Tyr-Tyr) or the corresponding salt The content is 2.0 ppm/Brix (200 μg/100 g/Bx) or more, preferably 10 ppm/Brix or more, preferably 20 ppm/Brix or more, 8000 ppm/Brix or less, and preferably 800 ppm/Brix or less. 80ppm / Brix or less, typically 2.0 ~ 8000ppm / Brix, to 10 ~ 800ppm / Brix preferably, preferably 20 ~ 80ppm / Brix. The above content is also used in the case of using a cyclic dipeptide of a synthetic or purified product or a salt thereof. In the present invention, the content of the cyclic dipeptide or a salt thereof is as described above in terms of Brix (sugar degree: Bx) unit. The "Brix unit amount" in the present specification means an amount defined by the value of the mass percentage of the sucrose solution (sucrose containing only sucrose as a solute) at 20 °C. And, unless otherwise stated, the instructions used in this manual "ppm" means ppm by weight/capacity (w/v), and 1.0 ppm/Brix is 0.1% by weight in terms of a specific gravity of the solvent, and is converted to 0.01% by weight.

The content of the cyclic dipeptide or a salt thereof can be measured in accordance with a known method. For example, the measurement can be carried out using an LC-MS/MS or a sugar meter.

5-2. Mechanism of action

As described above, when carnitine dipeptidase 1 is inhibited, the concentration in the body of a mammal such as a carnitine which is decomposed by carnitine dipeptidase 1 can maintain or suppress the decrease in the concentration. As a carnitine, proton buffer activity, calcium secretion and calcium sensitivity control, antioxidant action, metal ion chelation, extracellular donor of histidine/histamine, hyperglycemia improvement, anti-inflammatory effect Inhibition of the formation of terminal glycation products, inhibition of cell death caused by cerebral ischemia, accumulation of amyloid β in Alzheimer's disease (AD) model mice, and immunomodulatory effects. Therefore, by maintaining the body concentration of carnitine at a high level, cognitive function reduction or prevention or improvement of Alzheimer's disease and autism can be obtained with schizophrenia such as the accumulation of amyloid β. The prevention or improvement effect of various diseases caused by diabetes or oxidative stress or the production of terminal glycation products which are effective in improving blood sugar can be obtained, and prevention or improvement of inflammation of blood vessels or tissues which is anti-inflammatory action can be obtained. The effect is based on the immunomodulatory effect, and the prevention or improvement effect of the reduction of immune function can be obtained.

5-3. Other ingredients

The carnitine dipeptidase 1 inhibiting composition of the present invention may contain such a form, and may contain any additive or any component which is usually used in addition to the cyclic dipeptide or a salt thereof. Examples of such additives and/or components include vitamins such as vitamins E and vitamin C, and physiologically active components such as minerals, nutrients, and flavors, and may be formulated as excipients and binders. An emulsifier, a tonicizing agent (isoterizing agent), a buffering agent, a dissolution aid, a preservative, a stabilizer, an antioxidant, a coloring agent, a coagulant, or a coating agent, but are not limited thereto.

5-4. Use

The carnitine dipeptidase 1 inhibitory composition of the present invention is characterized in that the cyclic dipeptide or a salt thereof is contained as an active ingredient, and the cyclic dipeptide or a salt thereof inhibits the activity of carnitine dipeptidase 1, The in vivo concentration of carnitine decomposed by carnitine dipeptidase 1 can maintain or inhibit the decrease in this concentration. Alzheimer's disease caused by reduced cognitive function, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or production of terminal glycation products by maintaining carnitine in the body at high concentrations Prevention or improvement of the disease or autism can be carried out effectively. Therefore, the composition of the present invention is a disease caused by a decrease in cognitive function, diabetes, a decrease in immune function, inflammation of blood vessels or tissues, oxidative stress or production of terminal glycation products, Alzheimer's disease, or autism. The composition for preventing or improving carnitine dipeptidase 1 is used for prevention or improvement. According to these uses, the carnitine dipeptidase 1 inhibitory composition of the present invention can be reduced in cognitive function, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or final saccharification. A composition for preventing or improving various diseases caused by the production of products, Alzheimer's disease or autism. In addition, the term "prevention or improvement" as used in the present specification includes both concepts of improving the current state or preventing the deterioration state due to the current state, and therefore includes terms such as treatment, reply, reduction, and relaxation. .

The carnitine dipeptidase 1 inhibiting composition of the present invention can be formulated into a solid preparation or a general liquid preparation or a suspension agent such as a tablet (containing a coated tablet), a granule, a powder, a powder or a capsule according to a known method. Or a liquid such as an emulsion. These compositions can be taken directly with water or the like. Further, after the preparation process is easy to add (for example, a powder form or a particle form), it can be used as a raw material of a pharmaceutical product, for example.

The carnitine dipeptidase 1 inhibitory composition of the present invention can be provided as an example of a drug, but is not limited to this form. The agent is provided directly as a composition or as a composition containing the agent. Examples of the composition of the present invention include a pharmaceutical composition, a food and beverage composition, a food composition, a beverage composition, a cosmetic composition, and the like, but are not limited thereto. Examples of the food composition include functional foods, health supplement foods, nutritional functional foods, special purpose foods, specific health foods, nutritional supplement foods, food for food therapy, health foods, supplements, and food additives. Wait.

The carnitine dipeptidase 1 inhibitor composition of the present invention can be applied to any of therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it may be exemplified by pharmaceuticals, medical products, cosmetics, and the like, or may not be a pharmaceutical law, but may be expressly or implicitly used as a cognitive function. Compositions such as reduction, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or the production of terminal glycation products, various diseases, Alzheimer's disease, or prevention or improvement effects of autism And the user.

The other aspect of the present invention relates to the carnitine dipeptidase 1 inhibitory composition which is expressed by a function of being inhibited by carnitine dipeptidase 1. The expression or the functional expression is not particularly limited, and examples thereof include "suppression of cognitive function reduction", "expectation of expected cognitive function", "increased increase in blood glucose level", "improvement of immune function", and "anticipation of antioxidant activity". "Action", "Reducing oxidative stress", "Expecting anti-glycation", "Reducing saccharification stress", "Suppressing inflammation of blood vessels", "Expecting prevention or improvement of Alzheimer's disease", "Expecting autism Prevention or improvement, etc., or may be considered as the same representation or functional representation. In the present specification, the expression and the functional expression may be attached to the composition itself or may be attached to the container or package of the composition.

The carnitine dipeptidase 1 inhibiting composition of the present invention can be ingested in an appropriate manner in accordance with the form. The method of ingestion is not particularly limited as long as the cyclic dipeptide of the present invention or a salt thereof can be transferred to circulating blood. For example, it is in the form of an oral liquid preparation such as an oral solid preparation, an internal liquid preparation or a syrup preparation, an injection preparation, an external preparation, a suppository, or a non-oral preparation such as a transdermal absorption agent, but is not limited thereto. In the present specification, "ingestion" means using a whole state including ingestion, taking or drinking.

The applicable amount of the carnitine dipeptidase 1 inhibitory composition of the present invention can be based on the form, the administration method, the purpose of use, and the patient to be administered It is not necessary to set the age, weight, and symptoms of the diseased animal. The effective human intake of the composition of the present invention is not constant. For example, the weight of the cyclic dipeptide or the salt thereof as the active ingredient is preferably 10 mg or more, preferably 100 mg or more, per day for a human having a body weight of 50 kg. . In addition, the administration can be carried out in a single or several times within one day for the desired amount of administration. The period of investment can also be arbitrary. In addition, the effective human intake of the composition of the present invention is the amount of the carnitine dipeptidase 1 inhibitory composition of the present invention which exhibits an effective effect on humans, and the type of the cyclic dipeptide contained in the composition. There is no particular limitation.

The object of application of the carnitine dipeptidase 1 inhibitory composition of the present invention is preferably human, but livestock animals such as cattle, horses, sheep, dogs, cats, rabbits, etc., or experimental animals such as rats, rats, guinea pigs, monkeys, and the like Also. When an animal other than human is administered as a subject, the mouse may be used in an amount of about 20 g per animal per day, depending on the content of the active ingredient in the composition, the state of the subject, the body weight, the sex, and the age. In contrast, the total amount of the cyclic dipeptide or a salt thereof is preferably 10 mg/kg or more, and preferably 100 mg/kg or more.

5-5. Combination with carnitine (combined)

The above specific cyclic dipeptide or a salt thereof can be used in combination with carnitine. Therefore, the present invention provides a composition in which the specific cyclic dipeptide or a salt thereof and carnitine are combined (hereinafter also referred to as "combination composition of the present invention").

By combining the above cyclic dipeptide or a salt thereof with carnitine The carnitine dipeptidase 1 blocking action of the cyclic dipeptide or a salt thereof can delay the decomposition of carnitine from carnitine dipeptidase 1, and can efficiently deliver the carnitine to the target tissue or organ. . Not only the carnitine originally present in the body, but also the carnitine dipeptidase 1 can be used to block the composition and carnitine, and the carcinine concentration can be further maintained, and the effect of carnitine can be effectively enhanced.

The composition for use in the present invention is a composition for inhibiting carnitine dipeptidase 1 by containing the above specific cyclic dipeptide or a salt thereof. Further, the combined composition of the present invention is preferably used in the use described in the above 5-4 from the viewpoint of enhancing the effect of carnitine. That is, the combined composition of the present invention preferably has various cognitive diseases, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or production of terminal glycation products, Alzheimer's disease or self A composition for the prevention or improvement of autism. The composition for co-production of the present invention may be a pharmaceutical composition, a food or beverage composition, a food composition, a beverage composition, a cosmetic composition or the like, but is not limited thereto. Examples of the non-food composition include functional foods, health supplement foods, nutritious functional foods, special purpose foods, specific health foods, nutritional supplement foods, foods for food therapy, health foods, supplements, and food additives. Wait.

The carnitine in the present invention is a dipeptide composed of β -alanine and histidine, which is also called β -alaninyl histidine. Although carnitine contains any of D body (D-carnitine), L body (L-carnitine), and DL body (DL-carnitine), in the present invention, L body (L-carnitine) and DL are used. The body (DL-carnitine) is preferred, and the L form (L-carnitine) is preferred. The CAS registration number of D body (D-carnitine) is 5853-00-9, and the CAS registration number of L body (L-carnitine) is 305-84-0.

The carnitine to be used in the present invention is not particularly limited, and may be any one of natural persons derived from animals or obtained by chemical synthesis or the like. In the present invention, it is preferred to use the sold carnitine. In addition, the content of the carnitine in the composition for use in the present invention is not particularly limited as long as the administration form, the administration method, and the like are considered, but the amount of the desired effect of the present invention can be obtained.

The ratio of the cyclic dipeptide or the salt thereof to the carnitine in the composition for use in the present invention is not particularly limited as long as the ratio of the desired effect of the present invention can be obtained. For example, the ratio (cyclic dipeptide or its salt: carnitine) in the composition of the present invention is preferably from 1:950 to 1:1, preferably from 1:950 to 1:5. It is 1:900~1:10.

6. Use of a cyclic dipeptide or a salt thereof for blocking carnitine dipeptidase 1

One aspect of the present invention is the use of carnitine dipeptidase 1 which hinders a specific cyclic dipeptide or a salt thereof having an amino acid as a constituent unit. Preferably, the barrier is selected from the group consisting of Cyclo(Lys-Lys), Cyclo(Ile-Glu), and cycloisoleucine. Amine acid [Cyclo(Ile-Lys)], cyclo-leucine tyrosine acid [Cyclo (Leu-Tyr)], cyclomethicin-decyl glutamic acid [Cyclo (Met-Val)], cycloisoleucine Cyclo(Ile-Thr), cycloglutamine leucine (Cyclo(Glu-Leu)), cyclosamine, Cyclo(Arg-Ile), ring Tryptophan thioglycolic acid (Trp-Tyr)], Cyclo(Phe-Trp), Cyclo(Asn-Leu), cyclomethicone-based fluorenyl Amine acid (Cyclo(Met-Ile)], cycloisoleucine, Cyclo(Ile-Tyr), cyclomethicone, Cyclo(Met-Ser), cyclodecylamine Cyclo(Val-Thr), Cyclo(Val-Lys), Cyclo(Thr-Glu), and Cyclosulphate Use of carnitine dipeptidase 1 of one or two or more cyclic dipeptides or a salt thereof in a group of tyrosine tyrosine (Cyclo(Tyr-Tyr)). It is preferred to use three or more selected from the above-mentioned cyclic dipeptide or a salt thereof for inhibiting carnitine dipeptidase 1.

In the use of the present invention, it contains various diseases caused by, for example, decreased cognitive function, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress or production of terminal glycation products, Alzheimer's disease or self The use of the above-mentioned cyclic dipeptide or a salt thereof for preventing or improving the disease is not limited thereto. Moreover, the use is for human or non-human animals, and can be used therapeutically or non-therapeutic. The term "non-therapeutic" means that there is no medical action, that is, the concept of treating the human body's handling behavior.

7. Method for blocking carnitine dipeptidase 1

One aspect of the present invention is a method of inhibiting carnitine dipeptidase 1 by using a specific cyclic dipeptide having a amino acid as a constituent unit or a salt thereof as an active ingredient. The method comprises a Cyclophosphamide-based lysine (Lys-Lys)], cycloisoleucine glutamic acid [Cyclo (Ile-Glu)], cycloisoleucine lysine lysine [Cyclo (Ile-Lys)], cycloleucine decyl tyramine Acid [Cyclo (Leu-Tyr)], cyclomethicin-proline glutamic acid [Cyclo (Met-Val)], cycloisoleucine, Cyclo (Ile-Thr), cycloglutamine Cyclo(Glu-Leu), cyclosamine, Cyclo(Arg-Ile), cycloamine tyrosine, Cyclo(Trp-Tyr), cyclic benzene Cyclo(Phe-Trp), Cyclo(Asn-Leu), cyclomethicone-based leucine (Met-Ile) 】, Cyclo(Ile-Tyr), cyclomethicone, Cyclo(Met-Ser), cyclomethamine, Cyclo (Val) -Thr)], Cyclo(Val-Lys), Cyclo(Thr-Glu), and cyclinate- tyrosine (Tyr-Tyr) A method of inhibiting carnitine dipeptidase 1 by using one or two or more cyclic dipeptides or a salt thereof in a group as an active ingredient. More preferably, it is a method of inhibiting carnitine dipeptidase 1 which is used as an active ingredient from three or more selected from the above-mentioned cyclic dipeptide or its salt.

The other aspect of the method is an inhibitory carnitine dipeptidase 1 which contains a specific cyclic dipeptide or a salt thereof as an active ingredient and which comprises a therapeutically effective amount, which is an inhibitor of carnitine dipeptidase 1 method. Containing a substance selected from the group consisting of Cyclo(Lys-Lys), Cyclo(Ile-Glu), Cycloisoleucine-lysine Cyclo(Ile-Lys)], cycloleucine thiol tyrosine [Cyclo (Leu-Tyr)], cyclomethamine decyl glutamic acid [Cyclo (Met-Val)], cycloisoleucine thiol threonine [Cyclo (Ile-Thr)], cycloglutamine decyl leucine Acid [Cyclo(Glu-Leu)], cyclosamine, Cyclo(Arg-Ile), cyclosamine tyrosine (Cyclo(Trp-Tyr)], cyclophenylpropylamine Cyclo(Phe-Trp), Cyclo(Asn-Leu), cyclomethicone, Cyclo(Met-Ile), ring Cyclo(Ile-Tyr), cyclomethicone, Cyclo(Met-Ser), cyclomethalin, Cyclo(Val-Thr) 】, Cyclo(Val-Lys), Cyclo(Thr-Glu), and tyrosine tyrosine [Cyclo(Tyr-) A method in which a group of one or two or more cyclic dipeptides or a salt thereof is administered as an active ingredient to inhibit carnitine dipeptidase 1 in a therapeutically effective amount is preferred. More preferably, it is a method of administering a therapeutically effective amount of the inhibitory carnitine dipeptidase 1 as an active ingredient, comprising three or more selected from the above-mentioned cyclic dipeptide or a salt thereof.

In the above method, the inhibition of carnitine dipeptidase 1 is the same as the above-mentioned application target of the carnitine dipeptidase 1 inhibitor composition of the present invention. In the present specification, the therapeutically effective amount is that when the carnitine dipeptidase 1 inhibitory composition of the present invention is administered to the above-mentioned subject, the carnitine dipeptidase 1 is inhibited as compared with the unadministered subject. The amount of carnitine decomposition activity. The specific effective amount can be appropriately set depending on the administration form, the administration method, the purpose of use, and the age, weight, and symptoms of the subject, and is not necessarily determined.

For the method of the present invention, the specific cyclic dipeptide or a salt thereof described above may be administered as a therapeutically effective amount as described above, either directly or as a composition containing a specific cyclic dipeptide or a salt thereof.

According to the method of the present invention, carnitine dipeptidase 1 can be inhibited without side effects.

[Examples]

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The skilled person can make various modifications and modifications to the method of the present invention, and these are also included in the scope of the present invention.

Example 1. Review of the effect of inhibition of serum carnosinase (CNDP1) activity by cyclic dipeptide

Various cyclic dipeptide standards are provided by the chemical synthesizer for testing. The human serum carnosine enzyme CNDP1 was recombinant Human Carnosine Dipeptidase 1/CNDP1 (R&D systems). Carnitine is manufactured by Tokyo Chemical Industry Co., Ltd. The inhibitory effect of serum carnosinase (CNDP1) activity was examined at room temperature by the following procedure.

In a 1.5 mL Eppendorf tube, 50 μL of a 2 ng/μL CNDP1 solution and 25 μL of a cyclic dipeptide solution dissolved in a buffer (50 mM Tris, pH 7.5) were added, and 25 μL of a 4 mM carnitine solution dissolved in the same buffer was added to start the reaction. . After the reaction solution was incubated at room temperature for 60 minutes, 50 μL of a 1% Trichloroacetic acid (TCA) (Sigma) aqueous solution dissolved in deionized water was added and mixed by vortexing. Stop the reaction. To the sample after the completion of the reaction, a 1.8 M aqueous sodium hydroxide solution (containing 10% DMSO) containing 5 mg/mL o-Phthaldialdehyde (OPA) (Sigma) was added, and after mixing, the mixture was further cultured at room temperature for 30 minutes. The L-histamine acid dilution series was prepared in a range of 15.625 to 250 μM using a buffer, and after adding TCA and OPA in the same manner, the culture was maintained at a constant temperature for 30 minutes as a standard curve solution. Further, a water containing DMSO having the same content rate was added as a control group instead of the cyclic dipeptide. The sample and the standard curve solution were added in a total amount to a 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 luminometer.

For the result, the fluorescence intensity in the sample in which the enzyme (CNDP1) was added to the buffer was subtracted, and the correction value was calculated. When the corrected value of the fluorescence intensity in the control group was taken as 100%, each of the cyclic dipeptides was tested. The corrected value of the fluorescence intensity in the sample was taken as CNDP1 residual viability (%). The results are shown in Table 1.

From the above results, it was found that the cyclic dipeptides shown in Table 1 all have an inhibitory effect on the activity of serum carnosine (CNDP1).

Example 2. Review of the effect of inhibition of serum myostatin (CNDP1) activity by linear dipeptide

The linear peptide of the known tissue myopeptidase (CNDP2) hindering activity was examined for its inhibitory effect on the activity of serum carnosinase (CNDP1). Various linear dipeptide standards were provided by the BACHEM company for testing. The other materials were also examined in the same manner as in Example 1 under the same method as in Example 1 for the inhibition of the activity of the serum dipeptide-serum serum myopeptidase (CNDP1). The results are shown in Table 2.

As shown in Table 2, even when the linear dipeptide which inhibits the activity of CNDP2 was set to have a concentration of 500 μM, the inhibitory effect of serum carnosinase (CNDP1) activity was not observed. From the results, it is known that the linear dipeptide which inhibits the activity of CNDP2 does not have an inhibitory effect on the activity of serum carnosine (CNDP1). Further, from the above results, it is known that the CNDP2 inhibitory activity of the cyclic dipeptide shown in Table 1 is a known linear chain. The dipeptides are heterogeneous structures that block the activity of serum carnosinase (CNDP1), and are not related to the inhibitory substances of CNDP1 and the inhibitory substances of tissue myopeptidase (CNDP2).

[Industrial availability]

The present invention provides a carnitine dipeptidase 1 inhibitory composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient. The present invention provides a novel means for prevention or improvement such as reduction in cognitive function, and thus has high industrial applicability.

Claims (10)

A composition for inhibiting carnitine dipeptidase 1 which is a composition for inhibiting carnitine dipeptidase 1 containing a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, and is characterized by the aforementioned The cyclic dipeptide or a salt thereof is selected from the group consisting of Cyclo(Lys-Lys), Cyclo(Ile-Glu), Cycloisoleucine Cyclo(Ile-Lys), Cyclo(Leu-Tyr), cyclomethicin [Cyclo(Met-Val)], ring Cyclo(Ile-Thr), Cyclo(Glu-Leu), Cyclo(Arg-Ile) 】, cyclosamine tyrosine acid [Cyclo (Trp-Tyr)], cyclophenylalanine phthalic acid [Cyclo (Phe-Trp)], cycloaspartic acid leucine [Cyclo (Asn-) Leu)], cyclomethicone-based leucine (Met-Ile), cycloisoleucine- tyrosine (Cyclo (Ile-Tyr)), cyclomethicin-based tyrosine [Cyclo(Met-Ser)], cyclomethamine-threonine [Cyclo(Val-Thr)], cyclomethamine lysine lysine [Cyclo One or two groups of (Val-Lys)], cyclosulphate glutamic acid [Cyclo (Thr-Glu)], and cyclo tyrosine tyrosine (Cyclo (Tyr-Tyr)] The above. The carnitine dipeptidase 1 inhibitory composition of claim 1, which is used for various diseases caused by decreased cognitive function, diabetes, decreased immune function, inflammation of blood vessels or tissues, oxidative stress, or production of terminal glycation products. Prevention or improvement of Alzheimer's or autism. The carnitine dipeptidase 1 hindering composition according to claim 1 or 2, The medium cyclic dipeptide or a salt thereof is derived from a peptide derived from an automatic plant. The carnitine dipeptidase 1 inhibitory composition according to any one of claims 1 to 3, wherein the cyclic dipeptide or a salt thereof is contained in an amount of 200 μg/100 g/Bx or more. The carnitine dipeptidase 1 inhibitory composition according to any one of claims 1 to 3, wherein the cyclic dipeptide or a salt thereof is contained in an amount of 1000 μg/100 g/Bx or more. The carnitine dipeptidase 1 inhibitory composition according to any one of claims 1 to 5, which is represented by a function which is inhibited by carnitine dipeptidase 1. The composition of claim 6, wherein the functional expression is selected from the group consisting of "reducing the reduction of cognitive function", "predicting the maintenance of cognitive function", "increasing the blood sugar level", "improving the immune function", "expecting the antioxidant effect", "Reducing oxidative stress", "expecting anti-glycation", "reducing saccharification stress", "inhibiting inflammation of blood vessels", "expecting prevention or improvement of Alzheimer's disease" and "expecting prevention of autism or Improve the group of people. The carnitine dipeptidase 1 inhibitory composition according to any one of claims 1 to 7, wherein the composition is a drug. Use of a cyclic dipeptide or a salt thereof for inhibiting carnitine dipeptidase 1 with an amino acid as a constituent unit, characterized in that the cyclic dipeptide or a salt thereof is selected from the group consisting of cyclolylamine Amine acid [Cyclo(Lys-Lys)], cycloisoleucine glutamic acid [Cyclo (Ile-Glu)], cycloisoleucine lysine lysine [Cyclo (Ile-Lys)], cycloleucine Mercapto Amine acid [Cyclo(Leu-Tyr)], cyclomethicin-decyl glutamic acid [Cyclo(Met-Val)], cycloisoleucine thiol-threonine [Cyclo(Ile-Thr)], cycloglutamine Cyclo(Llu-Leu), Cyclo(Arg-Ile), Cyclo(Trp-Tyr), ring Phenylaminotryptophanic acid [Cyclo(Phe-Trp)], cycloalkane leucine (Cyclon (Asn-Leu)], cyclomethicone thiol isoleucine [Cyclo (Met-Ile) )], Cyclo(Ile-Tyr), cyclomethicone, Cyclo(Met-Ser), cyclomethamine-threonine Val-Thr)], cyclomethamine lysine (Cyclo-Val), cyclosulphate glutamic acid [Cyclo(Thr-Glu)], and cyclic tyramine tyrosine] One or two or more groups of Cyclo (Tyr-Tyr). A method for using a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, which inhibits carnitine dipeptidase 1, characterized in that the cyclic dipeptide or a salt thereof is selected from the group consisting of lysine Cyclo(Lys-Lys), cycloheximide glutamic acid [Cyclo(Ile-Glu)], cycloisolysine lysine lysine [Cyclo(Ile-Lys)], Cyclo (Leu-Tyr), cyclomethicin quinone, Cyclo(Met-Val), cycloisoleucine, Cyclo (Ile-Thr) )], cycloglutamine leucine (Cyclo(Glu-Leu)], cyclosamine decyl isoleucine [Cyclo(Arg-Ile)], cyclosamine thioglycolic acid [Cyclo(Trp) -Tyr)], cyclophenylalanine phthalic acid [Cyclo(Phe-Trp)], cyclic aspartate Cyclo(Asn-Leu), cyclomethicone, Cyclo(Met-Ile), cycloheximyl tyrosine, Cyclo(Ile-Tyr), ring Cyclo(Met-Ser), Cyclo(Val-Thr), Cyclo(Val-Lys) One or two or more of the group consisting of cyclo sulphonyl glutamic acid [Cyclo (Thr-Glu)] and cyclo tyrosine tyrosine (Cyclo (Tyr-Tyr)].