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WO2013133032A1 - Inhibiteur de dipeptidyl peptidase-iv - Google Patents

Inhibiteur de dipeptidyl peptidase-iv Download PDF

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Publication number
WO2013133032A1
WO2013133032A1 PCT/JP2013/054292 JP2013054292W WO2013133032A1 WO 2013133032 A1 WO2013133032 A1 WO 2013133032A1 JP 2013054292 W JP2013054292 W JP 2013054292W WO 2013133032 A1 WO2013133032 A1 WO 2013133032A1
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pro
seq
ala
dipeptidyl peptidase
peptides
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PCT/JP2013/054292
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English (en)
Japanese (ja)
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明男 山田
琢磨 桜井
越智　大介
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森永乳業株式会社
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Priority to JP2013541089A priority Critical patent/JP5976004B2/ja
Publication of WO2013133032A1 publication Critical patent/WO2013133032A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4732—Casein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/485—Exopeptidases (3.4.11-3.4.19)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/14—Dipeptidyl-peptidases and tripeptidyl-peptidases (3.4.14)
    • C12Y304/14005—Dipeptidyl-peptidase IV (3.4.14.5)

Definitions

  • the present invention relates to a dipeptidyl peptidase-IV inhibitor and the like.
  • Dipeptidyl peptidase-IV (di- peptidyl peptidase-IV: hereinafter also referred to as “DPP-4”) is a multifunctional transmembrane glycoprotein having N-terminal dipeptidase activity. It is present on most mammalian cells and is present in various tissues such as the liver, kidney, small intestine, salivary gland, blood cells and plasma, so it is assumed that it has a broad role in vivo and is created. It is an enzyme that has recently attracted attention as a drug target.
  • Dipeptidyl peptidase-IV is known to be a degrading enzyme of glucagon-like peptide 1 (hereinafter referred to as “GLP-1”) and glucose-dependent insulinotropic polypeptide (hereinafter referred to as “GIP”) of incretin. ing.
  • GLP-1 glucagon-like peptide 1
  • GIP glucose-dependent insulinotropic polypeptide
  • the dipeptidyl peptidase-IV inhibitor having an action of inhibiting dipeptidyl peptidase-IV activity is expected to be used as an antidiabetic agent.
  • dipeptidyl peptidase-IV inhibitors are still a new genre of therapeutic agents compared to insulin secretion inhibitors, glucose absorption inhibitors, etc., and many new substances having dipeptidyl peptidase-IV inhibitory activity can be found. It is desired.
  • the first step in the treatment of diabetes is diet therapy and exercise therapy, and when the blood glucose level cannot be controlled even now, pharmaceuticals for treating diabetes are currently used. Therefore, if it is possible to provide a substance having dipeptidyl peptidase-IV inhibitory activity as a supplement or food additive, it is considered that it can contribute widely to the improvement of blood glucose level.
  • Patent Document 1 discloses that a bicyclic pyrimidine is used as a dipeptidyl peptidase-IV inhibitor for treating or preventing diabetes.
  • casein is subjected to alkaline decomposition by adjusting pH and temperature, and then various peptides such as proteases are further adjusted to separate and purify various peptides from hydrolyzed products.
  • a dipeptidyl peptidase-IV inhibitory action has been found among them.
  • dipeptidyl peptidase-IV inhibitors derived from food see, for example, Patent Documents 3 to 5).
  • isolated peptides obtained by isolating only one peptide from casein or whey hydrolyzate are IPI, LPL, KVLP, LPVPQK, VPLGTQ, VPYPQ, PLLQ, GPFP, LPVPQ, LPQYL, MPLW, YVPEPF, PQSVLS, PFP, LPVP, EMPFPK, LPLP, GPFPIIV, APFPE, HPIK and AFPPEVF are described, and dipeptidyl peptidase-IV inhibition test results of these isolated peptides are disclosed.
  • dipeptidyl peptidase-IV inhibitors have been disclosed in the past, for example, in Patent Document 1, an organic synthetic compound requires a complicated synthesis process, and future verification is necessary regarding safety. Any dipeptidyl peptidase-IV inhibitor should be studied, and the current situation is that the search for dipeptidyl peptidase-IV inhibitors is not sufficient.
  • search for novel peptides and various physiological activity of peptides have been conducted.
  • the present invention is to provide an excellent dipeptidyl peptidase-IV inhibitor.
  • SPAQ SEQ ID NO: 1
  • GPVR SEQ ID NO: 1
  • SPAQ SEQ ID NO: 2
  • GPVR SEQ ID NO: 3
  • APK SEQ ID NO: 4
  • tetrapeptide SPAQ SEQ ID NO: 1
  • tetrapeptide GPVR SEQ ID NO: 2
  • pentapeptide HPPHP SEQ ID NO: 3
  • tripeptide APK SEQ ID NO: 4
  • the 3-5 peptides of the present disclosure can also be provided as supplements or food additives. Therefore, it is considered that the peptide of the present disclosure can widely contribute to the improvement of blood glucose level. From the above, it can be said that the 3-5 peptides of the present disclosure are more effective substances with added value.
  • the present invention provides a dipeptidyl peptidase-IV inhibitor containing as an active ingredient one or more peptides selected from peptides consisting of any of the following amino acid sequences (a) to (d): is there.
  • A Ser-Pro-Ala-Gln
  • B Gly-Pro-Val-Arg
  • GPVR Gly-Pro-Val-Arg
  • C His-Pro-His-Pro-His
  • HPPHPH SEQ ID NO: 3
  • Ala-Pro-Lys (APK: SEQ ID NO: 4)
  • the peptide comprising the amino acid sequence of any of the following (a) to (c) of the present invention is a novel peptide.
  • Ser-Pro-Ala-Gln (SPAQ: SEQ ID NO: 1)
  • B Gly-Pro-Val-Arg
  • GPVR SEQ ID NO: 2
  • C His-Pro-His-Pro-His (HPPHPH: SEQ ID NO: 3)
  • the present invention provides a dipeptidyl peptidase-IV inhibitor, a blood glucose level increase inhibitor, a hyperglycemia improving agent, and a vascular endothelial disorder inhibitor because the 3-5 peptides of the present disclosure have an excellent dipeptidyl peptidase-IV inhibitory action. Etc. can be provided.
  • the peptide of the present disclosure is a peptide having an amino acid sequence represented by SEQ ID NOs: 1 to 5 having a dipeptidyl peptidase-IV inhibitory action.
  • Examples of the peptide comprising 3 to 5 amino acid residues of the present disclosure include the following.
  • a peptide consisting of Ser-Pro-Ala-Gln (hereinafter referred to as “SPAQ”): and a peptide consisting of Gly-Pro-Val-Arg (SEQ ID NO: 2) (hereinafter referred to as “GPVR”).
  • HPPHP His-Pro-His-Pro-His
  • HPPHP a peptide composed of His-Pro-His-Pro-His
  • HPPHP a peptide composed of Ala-Pro-Lys
  • SPAQ, GPVR and APK are peptides containing one L-proline residue
  • HPPHPH is a peptide containing two L-proline residues.
  • Ser (S) is an L-serine residue
  • Pro (P) is an L-proline residue
  • Ala (A) is an L-alanine residue
  • Gln (Q) is an L-glutamine residue.
  • Gly (G) is L-glycine residue
  • Val (V) is L-valine residue
  • Arg (R) is L-arginine residue
  • His (H) is L-histidine residue
  • Lys (K) is L-lysine residues are indicated.
  • the 3-5 peptide of the present disclosure may be a salt of this peptide.
  • the salts include alkali metals such as potassium and sodium; alkaline earth metals such as calcium and magnesium, and one or more of them may be used as appropriate.
  • a protein comprising one or more amino acid sequences selected from the amino acid sequences represented by SEQ ID NO: 1 (SPAQ), SEQ ID NO: 2 (GPVR), SEQ ID NO: 3 (HPPHP), and SEQ ID NO: 4 (APK) Or peptides obtained by hydrolyzing the peptide and separating and purifying it from the resulting degradation product; after synthesizing 3 to 5 peptides of the present disclosure by the chemical synthesis method of the peptide, A method of separating and purifying the disclosed 3 to 5 peptide; a method of extracting from a plant, animal or microorganism producing the 3 to 5 peptide of the present disclosure and a peptide containing the peptide, and separating and purifying from the obtained extract, etc. Is mentioned
  • the 3-5 peptide of the present disclosure can be produced, for example, by appropriately hydrolyzing a protein such as casein with an acid alkali or an enzyme.
  • a method for obtaining the peptide by hydrolyzing a raw material protein with a hydrolase is exemplified. First, before hydrolyzing a raw material protein with an enzyme, the protein is dissolved, dispersed or suspended in water.
  • the starting protein is a protein containing at least one of the amino acid sequences represented by SEQ ID NOs: 1 to 4, and can produce the 3-5 peptides of the present disclosure when appropriately digested with a hydrolase.
  • the protein include those derived from animals and microorganisms, and casein that is available in large quantities is preferable.
  • the treatment method varies depending on the properties of the raw protein, but if the raw protein is soluble, the raw protein may be dispersed and dissolved in water or warm water, and if it is poorly soluble, the protein will be dissolved in hot water. May be homogenized by mixing and stirring.
  • an alkaline agent or an acid agent may be added to the solution containing the protein to adjust the pH.
  • This pH is preferably adjusted to the optimum pH of the hydrolase used or in the vicinity thereof. It does not specifically limit as said alkali agent or acid agent, What is necessary is just to use what is accept
  • the alkali agent include hydroxides such as sodium hydroxide and calcium hydroxide; carbonates such as potassium carbonate, and the like, and these may be alkali metal salts or alkaline earth metal salts.
  • the acid agent include inorganic acids such as hydrochloric acid and phosphoric acid; organic acids such as citric acid, acetic acid, and formic acid. Of these, one or more may be used as appropriate. In addition, it is desirable from the viewpoint of preventing deterioration due to contamination with various bacteria that the protein-containing solution is sterilized by heating at 70 to 90 ° C. for about 15 seconds to 10 minutes.
  • a predetermined amount of hydrolase is added to the solution containing the protein and reacted at a temperature of about 10 to 85 ° C. for 0.1 to 48 hours to obtain a hydrolyzate.
  • the solution is maintained at an appropriate temperature according to the type of the enzyme, for example, 30 to 60 ° C., preferably 45 to 55 ° C. to start protein hydrolysis. Is desirable.
  • the hydrolysis reaction time may be continued until the desired decomposition rate is reached while monitoring the decomposition rate of the enzyme reaction.
  • the degradation rate of the raw protein is preferably 20-60%.
  • the degradation rate of the starting protein is 20 ⁇ 30% is desirable.
  • the degradation rate of the raw material protein is 40 to 60%.
  • the hydrolase reaction is stopped, for example, by deactivation of the enzyme in the hydrolyzate, and can be performed by a heat deactivation treatment by a conventional method.
  • the heating temperature and holding time of the heat deactivation treatment can be appropriately set in consideration of the thermal stability of the enzyme used, and can be set as appropriate under conditions that can be sufficiently deactivated, for example, at a temperature range of 80 to 130 ° C. for 30 minutes. It can be performed with a holding time of ⁇ 2 seconds.
  • the hydrolase is not particularly limited, but is preferably an enzyme that can hydrolyze the raw protein to produce the peptide of the present disclosure.
  • the enzyme that can be produced is preferably an endopeptidase.
  • endopeptidases examples include those derived from microorganisms and animals. Specific examples include proteases derived from bacteria belonging to the genus Bacillus, bacteria derived from Aspergillus, and proteases derived from animal pancreas. . A commercially available protease can be used. Examples of commercially available proteases include proteases derived from Bacillus bacteria such as biopulase sp-20 (manufactured by Nagase Seikagaku) and protease N (manufactured by Amano Enzyme); PTN 6.0S (manufactured by Novozymes Japan), etc. Animal pancreatic proteases and the like can be exemplified as preferable ones.
  • proteases derived from Aspergillus bacteria such as protease A (manufactured by Amano Enzyme); animal pancreatic proteases such as pancreatin (manufactured by Amano Enzyme) and the like can be exemplified as preferable examples.
  • protease A manufactured by Amano Enzyme
  • animal pancreatic proteases such as pancreatin (manufactured by Amano Enzyme) and the like
  • protease derived from a bacterium belonging to the genus Bacillus it is preferably added at a rate of 100 to 5000 active units per gram of protein.
  • a protease derived from animal pancreas it is desirable to add it at a rate of 3000 to 8000 active units per gram of protein.
  • the purification of the 3-5 peptide of the present disclosure is usually performed in the same manner as that used for the purification of oligopeptide, such as ion exchange chromatography, adsorption chromatography, reverse phase chromatography, partition chromatography, gel filtration chromatography. It can be carried out by appropriately combining various types of chromatography such as chromatography, solvent precipitation, salting out, and distribution between two liquid phases.
  • the fraction containing the target substance can be determined using the dipeptidyl peptidase-IV inhibitory action described below as an index. Moreover, the active ingredient of those fractions can be identified by mass spectrometry.
  • the proteolytic product obtained by hydrolase is one or more selected from SPAQ (SEQ ID NO: 1), GPVR (SEQ ID NO: 2), HPPHP (SEQ ID NO: 3) and APK (SEQ ID NO: 4). What is included is preferable.
  • the 3-5 peptides of the present disclosure can also be produced by chemical synthesis.
  • the chemical synthesis of 3-5 peptides of the present disclosure can be performed by a liquid phase method or a solid phase method generally used for oligopeptide synthesis.
  • the synthesized peptide is deprotected as necessary, and unreacted reagents and by-products can be removed to isolate the 3-5 peptides of the present disclosure.
  • Such peptide synthesis can be performed using a commercially available peptide synthesizer.
  • the fact that the target peptide was obtained can be confirmed using the dipeptidyl peptidase-IV inhibitory action described later as an index.
  • the 3-5 peptides of the present disclosure have a dipeptidyl peptidase-IV inhibitory action, as shown in Examples below.
  • Dipeptidyl peptidase-IV may cause various diseases and symptoms by decomposing compounds involved in physiological functions in vivo. For this reason, inhibition of dipeptidyl peptidase-IV takes advantage of dipeptidyl peptidase-IV by utilizing the fact that the life span of compounds involved in physiological functions in vivo that have been degraded by dipeptidyl peptidase-IV is extended. Prevention, amelioration, or treatment of the disease or symptom that occurs.
  • Examples of the compound involved in the physiological function include glucagon-like peptide 1 (GLP-1) of incretin and glucose-dependent insulinotropic polypeptide (GIP). And by inhibiting the degradation of glucagon-like peptide 1 of this incretin, glucose-induced stimulation of insulin biosynthesis and secretion, glucagon secretion inhibition, regulation of gene expression, nutritional effects on sputum cells, suppression of food intake, In addition, it is possible to achieve various actions such as slowing of gastric emptying. This can contribute to normalization of the elevated blood glucose level and improvement / adjustment of hunger and body weight.
  • GLP-1 glucose-dependent insulinotropic polypeptide
  • dipeptidyl peptidase-IV reduces the function of vascular endothelial cells and damages vascular endothelial cells.
  • This decrease in blood vessel endothelial function or damage causes vascular disorders such as vasoconstriction, arteriosclerosis, and thrombus formation due to increased vascular tension, and these causes cause organ blood flow disorders, organ dysfunction, and diabetes. Complications will be induced.
  • dipeptidyl peptidase-IV inhibitors for example, see References 2 to 5 [Reference 2] Endocrine Journal 2011, 58 (1), 69-73. [Reference 3] J Am Coll Cardiol.
  • dipeptidyl peptidase-IV inhibitors In order to break this vicious circle, a combination of dipeptidyl peptidase-IV inhibitors and angiotensin converting enzyme inhibitors has been tried, and dipeptidyl peptidase-IV inhibitors also play an important role in the treatment of cardiovascular system It is considered a thing.
  • the 3-5 peptide of the present disclosure has a dipeptidyl peptidase-IV inhibitory action, the blood sugar level elevation inhibiting action, the hyperglycemia improving action, the vascular endothelial function lowering inhibiting action, the vascular endothelial disorder inhibiting action, the vascular disorder inhibiting action And vascular endothelial cell protective effect and appetite suppression effect.
  • the 3-5 peptides of the present disclosure are considered to be capable of suppressing appetite and protecting vascular endothelial cells.
  • “suppressing the increase in blood glucose level” here means including a decrease in blood glucose level, and particularly means “being able to lower a blood glucose level that is higher than a normal value or higher than necessary”.
  • the determination of the normal value of the blood glucose level may be based on the 2010 diagnostic criteria of the Japan Diabetes Society. Furthermore, it is considered that the diseases and symptoms caused by dipeptidyl peptidase-IV can be prevented, ameliorated, or treated by inhibiting dipeptidyl peptidase-IV with the peptides 3 to 5 of the present disclosure. Therefore, the peptides 3 to 5 of the present disclosure are used in a method for preventing, ameliorating, and / or treating diseases and symptoms caused by dipeptidyl peptidase-IV by ingesting or administering to animals including humans. be able to.
  • Examples of various diseases and symptoms caused by dipeptidyl peptidase-IV of the present disclosure include hyperglycemia, diabetes, diabetic complications, vascular endothelial disorder, and vascular disorder.
  • the various diseases caused by dipeptidyl peptidase-IV may be various diseases mediated by dipeptidyl peptidase-IV.
  • various diseases caused by hyperglycemia, diabetes and hyperglycemia conditions include, for example, diabetic microangiopathy (eg retinopathy, nephropathy, neuropathy, etc.) and macrovascular complications (eg angina) Ischemic heart disease such as symptom / myocardial infarction, cerebral infarction, obstructive arteriosclerosis, gangrene, etc.).
  • dipeptidyl peptidase-IV inhibitor can be used as a prophylactic or therapeutic agent for the above-mentioned various diseases is as disclosed in the aforementioned Patent Documents 1 to 5 and Reference Documents 2 to 5. It goes without saying that the disclosed 3-5 peptides can also be implemented as preventive and therapeutic agents for the various diseases.
  • the 3-5 peptide of the present disclosure may be used for dipeptidyl peptidase-IV inhibition, blood glucose level increase suppression, hyperglycemia improvement, vascular endothelial disorder suppression, anti-diabetes and the like as described above, In addition, it can be used in various preparations intended for use as described above, such as dipeptidyl peptidase-IV inhibitors, blood sugar level increase inhibitors, vascular endothelial disorder inhibitors, and antidiabetic agents. Can be used to
  • the 3-5 peptide of the present disclosure and the above-mentioned various preparations containing this as an active ingredient are ingested or administered to animals including humans.
  • the dipeptidyl peptidase-IV inhibitor etc. are ingested or administered to animals including humans.
  • prevention, improvement and / or treatment of hyperglycemia, diabetes (especially type 2 diabetes) and diabetic complications for example, diabetic vascular endothelial disorder and nephropathy), vascular endothelial disorder, vascular disorder, etc.
  • 3-5 peptide and the above-mentioned various preparations containing this as an active ingredient are for humans or animals for the prevention, improvement and / or treatment of hyperglycemia, diabetes, vascular disorders and the like as described above. It can be used as an active ingredient of pharmaceuticals, quasi-drugs, external preparations for skin, cosmetics and foods. When blended in a pharmaceutical product, it can be an oral or parenteral agent.
  • dipeptidyl peptidase-IV inhibition blood glucose level increase It can be applied to functional foods based on physiological functions such as suppression and improvement of hyperglycemia, foods for the sick, and foods for specified health use.
  • the dipeptidyl peptidase-IV inhibitor, etc. as described above, is a human or veterinary drug, quasi-drug, or external skin for the prevention, improvement and / or treatment of hyperglycemia, diabetes, vascular disorders, etc. It can be blended and used as an active ingredient of agents, cosmetics, foods and the like.
  • the present disclosure 3-5 peptide and the above-mentioned various preparations containing this as an active ingredient may be either oral administration or parenteral administration, but oral administration is desirable.
  • Parenteral administration includes intravenous injection, rectal administration, inhalation and the like.
  • Examples of the dosage form for oral administration include tablets, capsules, troches, syrups, granules, acid agents, ointments and the like.
  • components such as excipients, pH adjusters, colorants, corrigents and the like that are usually used for formulation. it can.
  • the 3-5 peptide of the present disclosure may be used in combination with a drug having a dipeptidyl peptidase-IV inhibitory action and / or angiotensin converting enzyme inhibitory action, an antidiabetic drug, a hypoglycemic drug, etc. that are known or will be found in the future Is also possible.
  • a drug having a dipeptidyl peptidase-IV inhibitory action and / or angiotensin converting enzyme inhibitory action an antidiabetic drug, a hypoglycemic drug, etc. that are known or will be found in the future Is also possible.
  • a person who is diabetic or a reserve group thereof (the reserve group refers to a person who has not yet been diabetic but has a high blood glucose level) needs to pay attention to hypertension.
  • 3 to 5 peptides of the present disclosure are contained in a food as an active ingredient, and one embodiment of the above-described various preparations containing the 3 to 5 peptides of the present disclosure and this as an active ingredient has a dipeptidyl peptidase-IV action. It can also be processed as food. Examples of such foods include liquids, pastes, solids, powders, etc. In addition to tablet confectionery, liquid foods, feeds (including for pets), etc., for example, flour products, instant foods, processed agricultural products, Processed marine products, processed livestock products, milk / dairy products, fats and oils, basic seasonings, compound seasonings / foods, frozen foods, beverages, and other commercial products.
  • examples of the flour product include bread, macaroni, spaghetti, noodles, cake mix, fried flour, bread crumbs and the like.
  • examples of the instant foods include instant noodles, cup noodles, retort / cooked food, cooking canned food, microwave food, instant soup / stew, instant miso soup / soup, canned soup, freeze-dried food, and other instant foods.
  • examples of the processed agricultural products include canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, cereals (cereal processed products), and the like.
  • examples of the processed fishery products include canned fishery products, fish hams and sausages, fish paste products, marine delicacies, and tsukudani.
  • Examples of the processed livestock products include canned livestock, pastes, livestock ham, sausages and the like.
  • Examples of the milk / dairy products include processed milk, milk beverages, yogurts, lactic acid bacteria beverages, cheese, ice creams, prepared powdered milks, creams, and other dairy products.
  • Examples of the fats and oils include butter, margarines, and vegetable oils.
  • the basic seasonings include soy sauce, miso, sauces, tomato processed seasonings, mirins, vinegars, etc.
  • the combined seasonings and foods include cooking mixes, curry ingredients, sauces, Examples include dressings, noodle soups, spices, and other complex seasonings.
  • Examples of the frozen food include raw material frozen food, semi-cooked frozen food, cooked frozen food, and the like.
  • the confectionery examples include caramel, candy, chewing gum, chocolate, cookies, biscuits, cakes, pie, snacks, crackers, Japanese confectionery, rice confectionery, bean confectionery, dessert confectionery, and other confectionery.
  • the beverages include carbonated beverages, natural fruit juices, fruit juice beverages, soft drinks with fruit juices, fruit drinks, fruit drinks with fruits, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks Sports drinks, nutritional drinks, alcoholic drinks, other taste drinks, and the like.
  • examples of commercially available foods other than the above include baby foods, sprinkles, and tea paste.
  • the blending amount of the 3-5 peptide of the present disclosure is preferably at least 0.001% by mass with respect to the final composition of the preparation.
  • the dose of the 3-5 peptide of the present disclosure varies depending on age, symptoms, etc., but is usually 0.001 to 3000 mg / day, preferably 0.01 to 30 mg / day, and is once to three times a day. May be administered separately.
  • Production Example 1 Production of tetrapeptide SPAQ, tetrapeptide GPVR, pentapeptide HPPHPH and tripeptide APK by enzymatic degradation of casein ⁇ Enzymatic degradation of casein 1> 900 g of water is added to 100 g of commercially available casein (manufactured by New Zealand Daily Board), well dispersed, sodium hydroxide is added to adjust the pH of the solution to 7.0, and the casein is completely dissolved. An aqueous casein solution was prepared. The casein aqueous solution was sterilized by heating at 85 ° C.
  • biolase sp-20 manufactured by Nagase Seikagaku Corporation 100 , 800 active units (1,200 active units per gram of protein), protease N (manufactured by Amano Enzyme) 168,000 active units (2,000 active units per gram of protein), and PTN 6.0S (manufactured by Novozymes Japan)
  • the hydrolysis reaction was initiated by adding 588,000 active units (7,000 active units per gram of protein).
  • the enzyme reaction was stopped by heating at 80 ° C. for 6 minutes to deactivate the enzyme, and then cooled to 10 ° C.
  • This hydrolyzed solution was ultrafiltered through an ultrafiltration membrane (manufactured by Asahi Kasei Co., Ltd.) having a molecular weight cut-off of 10,000, concentrated and freeze-dried to obtain 87 g of a freeze-dried product (casein enzyme degradation product 1).
  • HPLC condition 1 Column: Cadenza CD-C18 10 mmI. D. ⁇ 250mm (manufactured by Intact Corporation) Detection: UV 215nm Flow rate: 3 ml / min Eluent A: Aqueous solution containing 0.2% FA Eluent B: Acetonitrile solution containing 0.2% FA From 98% of Eluent A, 75% after 30 minutes, 50% after 40 minutes The hydrolyzate was separated under a gradient condition of 20% after 43 minutes, and the eluate was fractionated every 0.75 ml.
  • this compound was found to have a structure of HPPHPH (SEQ ID NO: 3).
  • the structures of active peak compounds 2 to 3 of the peptide having dipeptidyl peptidase-IV inhibitory ability are GPVR and HPPHPH.
  • casein enzyme degradation product 2 The obtained “casein enzymatic degradation product 2” was measured for dipeptidyl peptidase-IV inhibitory activity according to the above-mentioned ⁇ Peptide separation by HPLC> and was eluted at a retention time of 8.5 minutes for the first HPLC separation.
  • the fraction eluted at the retention time of 16.25 minutes of the second HPLC separation showed a strong dipeptidyl peptidase-IV inhibitory activity.
  • the 50% inhibitory concentration of enzyme activity in this fraction was 11 ⁇ g / ml.
  • the active peak compound 4 was obtained from the above-mentioned fraction in which the strong dipeptidyl peptidase-IV inhibitory activity was recognized.
  • this compound 4 was found to have a structure of tripeptide APK (SEQ ID NO: 4). All amino acid residues of Compound 4 were L-type. Thus, it was revealed that the structure of active peak compound 4 of the peptide having dipeptidyl peptidase-IV inhibitory ability is APK.
  • Production Example 2 Chemical synthesis of 3 to 5 peptides of SPAQ (SEQ ID NO: 1), GPVR (SEQ ID NO: 2), HPPH (SEQ ID NO: 3), APK (SEQ ID NO: 4) Peptide synthesizer (Model 433A, Applied Biosystems) ), Fmoc-Val (Peptide Research Laboratories)), Fmoc-Pro (Peptide Research Laboratories), Fmoc-Ala (Peptide Research Laboratories), Fmoc-Gln-Wang-PEG Resin Peptide SPAQ was synthesized by solid phase synthesis using (Watanabe Chemical Co., Ltd.) as a raw material.
  • the operation was performed according to the manual of Applied Biosystems and then deprotected.
  • This peptide was purified by the above HPLC condition 1.
  • VPP SEQ ID NO: 5
  • IPP Ile-Pro-Pro
  • LY Leu-Tyr
  • Test Example 1 Dipeptidyl peptidase-IV inhibitory activity confirmation test of each peptide The dipeptidyl peptidase-IV inhibitory activity confirmation test of each peptide obtained in Production Example 2 shown in Table 1 was conducted, and the results are shown in Table 1. .
  • Tetrapeptide SPAQ, tetrapeptide GPVR, pentapeptide HPPHP and tripeptide APK had dipeptidyl peptidase-IV inhibitory action.
  • the enzymatic degradation product of casein including SPAQ (SEQ ID NO: 1), GPVR (SEQ ID NO: 2), HPPHH (SEQ ID NO: 3) and APK (SEQ ID NO: 4) is a material having a dipeptidyl peptidase-IV inhibitory action or the like It is considered that it can be used for food, medicine, etc. as food.
  • Morinaga Milk Peptide MKP manufactured by Morinaga Milk Industry Co., Ltd.
  • APK was recognized by CU5000 (made by Morinaga Milk Industry Co., Ltd.).
  • the 50% inhibitory concentration of Morinaga Milk Peptide MKP (manufactured by Morinaga Milk Industry) for dipeptidyl peptidase-IV inhibition was 356 ⁇ g / ml.
  • SPAQ, GPVR and HPPHP are thought to contribute to the dipeptidyl peptidase-IV inhibitory action of Morinaga Milk Peptide MKP (manufactured by Morinaga Milk Industry).
  • the 50% inhibitory concentration of CU5000 (manufactured by Morinaga Milk Industry Co., Ltd.) for dipeptidyl peptidase-IV inhibition was 84 ⁇ g / ml.
  • APK is considered to contribute to the dipeptidyl peptidase-IV inhibitory action of the casein degradation product of CU5000 (manufactured by Morinaga Milk Industry Co., Ltd.).
  • DPP-4 inhibitory activity Measurement of dipeptidyl peptidase (DPP-4) inhibition was performed according to the method of Kato et al. “Kato, T. et al. Biochem. Med. 19, p351, 1978”. Specifically, the enzyme reaction was performed using Recombinant Human DPPIV / CD26 (R & D Systems, Inc.) as the enzyme (DPP-4) and H-Gly-Pro-AMC (Biomol GmbH) as the substrate. To each well of a 96-well microplate (nunc 137101), add water or an aqueous solution of each concentration of the test substance or HPLC fraction, and add 20 ⁇ l of Tris-HCl (0.25 M, pH 8.0).
  • the total volume was adjusted to 80 ⁇ l. After stirring, the plate was warmed in a 37 ° C. incubator for about 10 minutes, 10 ⁇ l of DPP-4 solution and 10 ⁇ l of substrate solution were added (total volume 100 ⁇ l), and the reaction was started by stirring. A well to which water was added instead of the enzyme was used as a control. The enzyme reaction was measured using a microplate reader (SH-9000, Corona Electric Co., Ltd.) under the condition where the internal temperature was maintained at 37 ° C. (5 minute interval, ex360 nm / em460 nm).
  • Inhibition rate (%) 100% ⁇ [(Yb) / (Xa)] ⁇ 100%
  • X water + enzyme + substrate
  • Y test substance + enzyme + substrate a: water + substrate b: test substance + substrate
  • IC 50 was calculated by calculating back the concentration at which the inhibition rate of the enzyme was 50%.
  • 3-5 peptides (specifically SPAQ, GPVR, HPPHPH, APK) of the present disclosure can be isolated from casein hydrolyzate, they are highly safe and can be used for pharmaceuticals, foods, skins. It can be used in a wide range of fields such as external preparations and functional foods.
  • a dipeptidyl peptidase-IV inhibitor comprising a peptide having any one of the following amino acid sequences (a) to (d) as an active ingredient, and an increase in blood glucose level
  • SPAQ, GPVR, HPPHPH for prevention, amelioration, or treatment of diseases caused by dipeptidyl peptidase-IV, diseases caused by hyperglycemia, diabetes, vascular endothelial disorders or diseases caused by vascular disorders
  • One or more peptides selected from APK are used as active ingredients, diseases caused by dipeptidyl peptidase-IV, diseases caused by hyperglycemia, diabetes, vascular endothelial disorder or A method for preventing, improving or treating a disease caused by a vascular disorder.
  • SPAQ, GPVR for use in the prevention, amelioration or treatment of diseases caused by dipeptidyl peptidase-IV, diseases caused by hyperglycemia, diabetes or diseases caused by vascular endothelial or vascular disorders, One or more peptides selected from HPPHP and APK.
  • SPAQ, GPVR, HPPHH, and the like for prevention, amelioration, or treatment of diseases caused by dipeptidyl peptidase-IV, diseases caused by hyperglycemia, diabetes, or diseases caused by vascular endothelial disorder or vascular injury
  • the disease and / or symptom caused by the dipeptidyl peptidase-IV is selected from hyperglycemia, diabetes, diabetic complications, vascular endothelial disorder and vascular disorder.
  • a peptide comprising the amino acid sequence of any one of the following (a) to (c).
  • One or more peptides selected from SPAQ, GPVR, HPPHH and APK obtained by hydrolyzing casein and a method for producing the same.
  • One or more peptides selected from SPAQ, GPVR, HPPHPH and APK obtained by separating and purifying casein in the following steps and a method for producing the same.
  • A Performing with a hydrolase (preferably endopeptidase). It is preferably carried out under conditions of 10 to 85 ° C. and 0.1 to 48 hours.
  • B Separating and purifying the hydrolyzate by chromatography. Preferably, one or two kinds selected from ion exchange chromatography, reverse phase chromatography, partition chromatography and the like are used.

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Abstract

L'invention concerne un inhibiteur supérieur de dipeptidyl peptidase-IV et similaires. En particulier, l'invention concerne un inhibiteur de dipeptidyl peptidase-IV, un agent hypoglycémique et un inhibiteur de dysfonction endothéliale vasculaire, chacun comprenant, en tant que principe actif, un ou plusieurs peptides choisis parmi des peptides comprenant une des séquences d'acides aminés représentées par (a)-(d) : (a) Ser-Pro-Ala-Gln (SEQ ID NO : 1), (b) Gly-Pro-Val-Arg (SEQ ID NO : 2), (c) His-Pro-His-Pro-His (SEQ ID NO : 3) et (d) Ala-Pro-Lys (SEQ ID NO : 4). L'invention concerne également de nouveaux peptides comprenant l'une quelconque des séquences d'acides aminés représentées par (a)-(c) : (a) Ser-Pro-Ala-Gln (SEQ ID NO : 1), (b) Gly-Pro-Val-Arg (SEQ ID NO : 2) et (c) His-Pro-His-Pro-His (SEQ ID NO : 3).
PCT/JP2013/054292 2012-03-09 2013-02-21 Inhibiteur de dipeptidyl peptidase-iv WO2013133032A1 (fr)

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CN111592583A (zh) * 2020-06-11 2020-08-28 湖南科技大学 一种生物活性多肽及其在制备二肽基肽酶4抑制剂中的应用
CN114805479A (zh) * 2022-04-13 2022-07-29 锡林郭勒职业学院 一种具有二肽基肽酶ⅳ抑制活性的生物活性肽
CN115028706A (zh) * 2022-01-05 2022-09-09 昆明理工大学 马乳酪蛋白小分子肽在制备二肽基肽酶ⅳ抑制剂中的用途
CN115594735A (zh) * 2022-11-25 2023-01-13 深圳市维琪医药研发有限公司（Cn） 具有抗衰老作用的肽及其美容组合物或药用组合物和用途
CN119019492A (zh) * 2024-10-29 2024-11-26 中国科学院烟台海岸带研究所 螺旋藻源天然dpp-iv抑制肽及其制备方法和应用

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CN111592583A (zh) * 2020-06-11 2020-08-28 湖南科技大学 一种生物活性多肽及其在制备二肽基肽酶4抑制剂中的应用
CN111592583B (zh) * 2020-06-11 2022-09-06 湖南科技大学 一种生物活性多肽及其在制备二肽基肽酶4抑制剂中的应用
CN115028706A (zh) * 2022-01-05 2022-09-09 昆明理工大学 马乳酪蛋白小分子肽在制备二肽基肽酶ⅳ抑制剂中的用途
CN115028706B (zh) * 2022-01-05 2024-02-09 昆明理工大学 马乳酪蛋白小分子肽在制备二肽基肽酶ⅳ抑制剂中的用途
CN114805479A (zh) * 2022-04-13 2022-07-29 锡林郭勒职业学院 一种具有二肽基肽酶ⅳ抑制活性的生物活性肽
CN114805479B (zh) * 2022-04-13 2024-02-13 锡林郭勒职业学院 一种具有二肽基肽酶ⅳ抑制活性的生物活性肽
CN115594735A (zh) * 2022-11-25 2023-01-13 深圳市维琪医药研发有限公司（Cn） 具有抗衰老作用的肽及其美容组合物或药用组合物和用途
CN115594735B (zh) * 2022-11-25 2023-09-22 深圳市维琪科技股份有限公司 具有抗衰老作用的肽及其组合物和用途
WO2024109878A1 (fr) * 2022-11-25 2024-05-30 深圳市维琪科技股份有限公司 Peptide ayant un effet anti-vieillissement, composition et utilisation associées
CN119019492A (zh) * 2024-10-29 2024-11-26 中国科学院烟台海岸带研究所 螺旋藻源天然dpp-iv抑制肽及其制备方法和应用

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