WO2017010537A1 - Composition qui contient un dipeptide dérivé de forme circulaire et qui inhibe la carnosinase sérique - Google Patents

Composition qui contient un dipeptide dérivé de forme circulaire et qui inhibe la carnosinase sérique Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
cyclo
ile
tyr
composition
lys
Prior art date
Application number
PCT/JP2016/070796
Other languages
English (en)
Japanese (ja)
Inventor
伸哉 富貴澤
斉志 渡辺
阿部　圭一
Original Assignee
サントリーホールディングス株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by サントリーホールディングス株式会社 filed Critical サントリーホールディングス株式会社
Priority to JP2017528720A priority Critical patent/JP6669750B2/ja
Publication of WO2017010537A1 publication Critical patent/WO2017010537A1/fr

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne une composition d'inhibiteur de carnosine dipeptidase 1, une utilisation de ladite composition qui inhibe la carnosine dipeptidase 1 et un procédé d'inhibition de la carnosine dipeptidase 1. La présente invention porte sur la découverte d'un dipeptide de forme circulaire spécifique ou d'un sel de celui-ci présentant une activité inhibitrice à l'encontre de la carnosine dipeptidase 1, et, par conséquent, fournit un moyen nouveau et efficace qui contribue à la prévention ou l'amélioration d'un déclin de la fonction cognitive ou analogue.
PCT/JP2016/070796 2015-07-16 2016-07-14 Composition qui contient un dipeptide dérivé de forme circulaire et qui inhibe la carnosinase sérique WO2017010537A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2017528720A JP6669750B2 (ja) 2015-07-16 2016-07-14 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

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015142091 2015-07-16
JP2015-142091 2015-07-16

Publications (1)

Publication Number Publication Date
WO2017010537A1 true WO2017010537A1 (fr) 2017-01-19

Family

ID=57757507

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/070796 WO2017010537A1 (fr) 2015-07-16 2016-07-14 Composition qui contient un dipeptide dérivé de forme circulaire et qui inhibe la carnosinase sérique

Country Status (3)

Country Link
JP (1) JP6669750B2 (fr)
TW (1) TW201717952A (fr)
WO (1) WO2017010537A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017119481A1 (fr) * 2016-01-08 2017-07-13 サントリーホールディングス株式会社 Composition contenant un dipeptide cyclique pour la prévention de maladie neurologiques
CN108546250A (zh) * 2018-04-04 2018-09-18 南京农业大学 环-l-谷氨酸-l-亮氨酸及其应用
WO2023120407A1 (fr) * 2021-12-23 2023-06-29 サントリーホールディングス株式会社 COMPOSITION POUR SUPPRIMER LA PRODUCTION ET/OU L'ACCUMULATION DE β-AMYLOÏDE
WO2023120408A1 (fr) * 2021-12-23 2023-06-29 サントリーホールディングス株式会社 Composition pour supprimer ou atténuer le déclin de la fonction cognitive
WO2023120405A1 (fr) * 2021-12-23 2023-06-29 サントリーホールディングス株式会社 COMPOSITION POUR RÉDUIRE AU MAXIMUM LA PRODUCTION ET/OU L'ACCUMULATION DE β-AMYLOÏDE

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010166911A (ja) * 2008-12-26 2010-08-05 Suntory Holdings Ltd 環状ジペプチド含有飲料
JP2011068652A (ja) * 2003-01-20 2011-04-07 Innovative Vision Products Inc カルノシナーゼ阻害剤とｌ−カルノシン類との併用および組成物
JP5690028B1 (ja) * 2014-06-20 2015-03-25 サントリーホールディングス株式会社 尿酸値低下剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011068652A (ja) * 2003-01-20 2011-04-07 Innovative Vision Products Inc カルノシナーゼ阻害剤とｌ−カルノシン類との併用および組成物
JP2010166911A (ja) * 2008-12-26 2010-08-05 Suntory Holdings Ltd 環状ジペプチド含有飲料
JP5690028B1 (ja) * 2014-06-20 2015-03-25 サントリーホールディングス株式会社 尿酸値低下剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BELLEZZA I. ET AL.: "Neuroinflammation and endoplasmic reticulum stress are coregulated by cyclo(His-Pro) to prevent LPS neurotoxicity", THE INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, vol. 51, 2014, pages 159 - 169, XP029026619 *
GRAZ C.J.M. ET AL.: "Cyclic Dipeptides in the Induction of Maturation for Cancer Therapy", J. PHARM. PHARMACOL., vol. 52, no. 1, 2000, pages 75 - 82, XP055345984 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017119481A1 (fr) * 2016-01-08 2017-07-13 サントリーホールディングス株式会社 Composition contenant un dipeptide cyclique pour la prévention de maladie neurologiques
CN108546250A (zh) * 2018-04-04 2018-09-18 南京农业大学 环-l-谷氨酸-l-亮氨酸及其应用
CN108546250B (zh) * 2018-04-04 2021-06-11 南京农业大学 环-l-谷氨酸-l-亮氨酸及其应用
WO2023120407A1 (fr) * 2021-12-23 2023-06-29 サントリーホールディングス株式会社 COMPOSITION POUR SUPPRIMER LA PRODUCTION ET/OU L'ACCUMULATION DE β-AMYLOÏDE
WO2023120408A1 (fr) * 2021-12-23 2023-06-29 サントリーホールディングス株式会社 Composition pour supprimer ou atténuer le déclin de la fonction cognitive
WO2023120405A1 (fr) * 2021-12-23 2023-06-29 サントリーホールディングス株式会社 COMPOSITION POUR RÉDUIRE AU MAXIMUM LA PRODUCTION ET/OU L'ACCUMULATION DE β-AMYLOÏDE

Also Published As

Publication number Publication date
TW201717952A (zh) 2017-06-01
JP6669750B2 (ja) 2020-03-18
JPWO2017010537A1 (ja) 2018-04-26

Similar Documents

Publication Publication Date Title
JP6669750B2 (ja) 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
JP2021020954A (ja) 動植物由来ペプチド含有血清カルノシン分解酵素阻害用組成物
JP2008539203A (ja) 新規栄養補助組成物
JPWO2011105435A1 (ja) 摂食障害治療剤
JP5926363B2 (ja) ジペプチジルペプチダーゼ−ｉｖ阻害剤
JP6857602B2 (ja) エンドセリン受容体拮抗用組成物
WO2017119481A1 (fr) Composition contenant un dipeptide cyclique pour la prévention de maladie neurologiques
WO2013133032A1 (fr) Inhibiteur de dipeptidyl peptidase-iv
WO2016133157A1 (fr) Inhibiteur de lipase
TW201733607A (zh) 神經性疾病之預防用組成物
CN107922458B (zh) 含有氨基酸及环状二肽的组合物
TW201716080A (zh) Ｔｒｐｖ１刺激用組成物
JP6661597B2 (ja) α−グルコシダーゼ阻害剤
US20220330595A1 (en) Angiotensin-converting enzyme inhibitor, blood pressure-lowering agent, and beverages and food products
JP6671367B2 (ja) 環状ジペプチド含有抗肥満用組成物
JP6684277B2 (ja) レニン−アンジオテンシン系抑制用組成物
WO2017014149A1 (fr) Composition contre l'obésité
WO2017014121A1 (fr) Composition pour antagoniste de récepteur d'hormone de concentration de mélanine
JP2023107887A (ja) 脳血流を増加させるための組成物
CN112638180A (zh) 用于短期肾功能的蛋白质水解产物
WO2017002765A1 (fr) Composition pour réduire les calories

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16824517

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017528720

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16824517

Country of ref document: EP

Kind code of ref document: A1