CN113801192B - Tetrapeptides for inhibiting dipeptidyl peptidase IV and application thereof - Google Patents
Tetrapeptides for inhibiting dipeptidyl peptidase IV and application thereof Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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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
- A61K38/07—Tetrapeptides
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- 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
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/81—Protease inhibitors
- C07K14/8103—Exopeptidase (E.C. 3.4.11-19) inhibitors
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- 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
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0006—Oxidoreductases (1.) acting on CH-OH groups as donors (1.1)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
- C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
- C12Y101/01001—Alcohol dehydrogenase (1.1.1.1)
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a tetrapeptide for inhibiting dipeptidyl peptidase IV and application thereof. The polypeptide of the invention comprises 4 amino acid residues, the molecular weight is 511.27, the theoretical isoelectric point is 3.70, and the amino acid sequence is as follows: tryptophan-proline-leucine-proline (Trp-Pro-Leu-Pro). The polypeptide of the invention is derived from an edible yeast enzymolysis product and can be prepared by solid phase synthesis. The polypeptide of the invention has good dipeptidyl peptidase IV inhibition activity and IC thereof 50 The value is 178.90 mu mol/L, and the sitagliptin has synergistic inhibition effect with low-dose sitagliptin (30% inhibition rate), can be used for developing and preparing medicaments with blood sugar reducing function, and has good application prospect.
Description
Technical Field
The invention relates to the field of functional foods, in particular to a tetrapeptide for inhibiting dipeptidyl peptidase IV and application thereof.
Background
Type II diabetes is a metabolic disease characterized by hyperglycemia, which can lead to serious complications such as micro-blood vessels and macro-blood vessels, and seriously endanger physical and mental health of patients. Dipeptidyl peptidase IV (DPP-IV) is increasingly becoming a major target for diabetes treatment due to its incretin insulin modulating effect. By inhibiting DPP-IV activity and improving half-life period of incretin, the aim of effectively controlling blood sugar can be achieved.
The artificially synthesized hypoglycemic drug has good hypoglycemic effect, but the side effect is not neglected. Such as causing adverse reactions such as hypoglycemia, weight gain, intestinal flatulence and diarrhea. Therefore, the DPP-IV inhibitor with good blood sugar reducing effect and lower toxic and side effects is developed and obtained, and urgent needs are provided for the prevention and treatment of type II diabetes.
Disclosure of Invention
The primary object of the present invention is to overcome the disadvantages and shortcomings of the prior art and to provide a tetrapeptide having DPP-IV inhibitory activity. The invention utilizes bacillus subtilis zymose preparation to hydrolyze edible yeast, takes DPP-IV inhibitory activity as an index, gradually enriches high-inhibitory active components by ethanol aqueous solution extraction and gel filtration chromatography, and the enriched components are identified by LC-MS/MS and screened to obtain tetrapeptides containing tryptophan-proline-leucine-proline (Trp-Pro-Leu-Pro). The tetrapeptides were synthesized in solid phase and found to have good inhibitory activity against DPP-IV.
Another object of the present invention is to provide the use of the tetrapeptides having DPP-IV inhibitory activity as described above.
Yet another object of the present invention is to provide a DPP-IV inhibitor or hypoglycemic agent.
The aim of the invention is achieved by the following technical scheme:
a tetrapeptide with DPP-IV inhibiting activity has an amino acid sequence of tryptophan-proline-leucine-proline (Trp-Pro-Leu-Pro).
The tetrapeptides having DPP-IV inhibitory activity may be prepared by means conventional in the art, for example by solid phase synthesis.
The application of the tetrapeptides with DPP-IV inhibitory activity in preparing DPP-IV inhibitors or hypoglycemic drugs.
The application of the tetrapeptide with DPP-IV inhibitory activity in combination with sitagliptin in preparation of DPP-IV inhibitor or hypoglycemic drugs.
In the application, the sitagliptin is present in a low dosage, specifically 75-85. Mu. Mol/L, more preferably 75-81. Mu. Mol/L, still more preferably 81. Mu. Mol/L.
The dosage of the tetrapeptide with DPP-IV inhibitory activity is 25-300 mu mol/L.
A DPP-IV inhibitor comprising the tetrapeptide having DPP-IV inhibitory activity described above.
The DPP-IV inhibitor also contains sitagliptin, wherein the sitagliptin exists at a low dosage, specifically 75-85 mu mol/L, and more preferably 81 mu mol/L.
A hypoglycemic agent contains the tetrapeptide with DPP-IV inhibitory activity.
The hypoglycemic medicine also contains sitagliptin, and the sitagliptin exists at a low dosage, specifically 75-85 mu mol/L, and more preferably 81 mu mol/L.
Compared with the prior art, the invention has the following advantages and effects:
1. the tetrapeptides of the invention have good DPP-IV inhibitory activity and half-inhibition rate IC of the tetrapeptides to DPP-IV 50 178.90. Mu. Mol/L.
2. The tetrapeptides of the invention have synergistic inhibition effect on DPP-IV activity with low-dose concentration sitagliptin.
3. The method is a small molecular polypeptide, has an easily-regulated structure, is easy to synthesize and modify, can obtain better activity, and has obvious application potential.
4. The tetrapeptides of the invention are derived from enzymatic hydrolysis products of edible yeasts, which are listed as food ingredients with general safety (GRAS) issued by FDA, and have high safety.
Drawings
FIG. 1 is a gel filtration chromatography separation spectrum.
FIG. 2 is a WPLP chromatogram of solid phase synthesis of tetrapeptides.
FIG. 3 is a mass spectrum of a WPLP for solid phase synthesis of tetrapeptides.
FIG. 4 is a graph showing the analysis of DPP-IV inhibition results of WPLP at different concentrations.
FIG. 5 is a two-reciprocal diagram of the polypeptide WPLP versus the Lineweaver-Burk of DPP-IV.
FIG. 6 is a graph showing the combined inhibition of polypeptide WPLP and the common hypoglycemic agent sitagliptin.
FIG. 7 is a graph showing the DPP-IV inhibitory activity analysis of a synthetic polypeptide derived from yeast hydrolysate.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
Example 1
The bacillus subtilis HU528 in this example was deposited at Guangdong province microbiological strain collection center, accession number GDMCC NO:60364, disclosed in chinese patent application CN 201810668986.8.
1. Enzyme preparation
Inoculating HU528 strain into solid culture medium (1% tryptone, 0.5% yeast extract, 1% NaCl,1.5% agar) by plate streaking method, culturing in 37 deg.C incubator upside down for 6 hr, inoculating single colony into seed culture medium (1% tryptone, 0.5% yeast extract, 1% sucrose, 0.0001% MgSO) 4 ,0.0001%CuSO 4 pH 7.0) and then cultured at 37℃under 200r/min for 6 hours (OD) 600 About 1.5). Inoculating the activated bacterial liquid into a 5L fermentation tank (0.75% glucose, 1.5% soybean meal powder, 0.075% CaCl) at 1.0% (v/v) 2 0.045% NaCl), fermenting and culturing for 54h under the conditions of 70% liquid loading, 37 ℃ fermentation temperature and 4L/min ventilation, centrifuging the obtained fermentation liquor at 4 ℃ for 10min at 8000 Xg, and removing thalli, wherein the fermentation supernatant is the enzyme preparation.
2. Enzyme Activity measurement
Protease activity was measured by the Fu Lin Fen method with reference to national standard GB/T23527-2009. First, a tyrosine standard curve (y=0.0077 x, r) was plotted with different concentrations of tyrosine 2 =0.999), the specific method for measuring the protease activity of the sample is as follows. And (3) centrifuging the fermentation liquor at room temperature (8000 Xg, 5 min), wherein the obtained supernatant is crude enzyme liquor. Taking 1mL of crude enzyme solution diluted by a certain multiple, adding 1mL of casein solution (2%, w/v) into a sample tube and a blank tube, reacting at 55 ℃ for 10min, adding 2mL of 0.4M trichloroacetic acid, and stopping reacting, and carrying out water bath at 55 ℃ for 20min; the blank tube was then first treated with 2mL of 0.4M trichloroacetic acid in a water bath at 55deg.C for 10min to inactivate the protease, and then with 1mL of casein solution (2%, w/v) in a water bath at 55deg.C for 20min. Centrifuging the blank tube and experimental tube at room temperature (8000 Xg, 5 min), sucking 1mL supernatant, adding 5mL 0.4M Na 2 CO 3 And 1mL of Fu Lin Fen reagent, after being fully mixed, the mixture is developed for 20min at 55 ℃, and absorbance is measured at 680nm by zeroing a blank tube. The measured OD values were used to obtain the corresponding tyrosine concentration by standard curve and the enzyme activity was calculated. Definition of enzyme activity unit: hydrolyzing casein at 55deg.C and pH 7.0 for 1min to give 1 μg tyrosineThe required enzyme amount is 1 enzyme activity unit, which is expressed as U/mL. Protease activity in the enzyme preparation was measured to be 4200U/mL.
3. Preparation, separation and identification of yeast DPP-IV inhibitory peptide
The enzyme preparation is added into edible yeast powder (from Guangdong Wuzhou pharmaceutical Co., ltd., dry yeast 2017, 6 month) according to the enzyme adding amount of 8000U/g yeast powder, and sterile water is added until the volume ratio (feed liquid ratio, w/v) of the edible yeast powder to the mixed liquid is 1:10. The pH of the mixture was adjusted to 8.0. After enzymolysis reaction for 4.5h at 55 ℃, enzyme is inactivated for 10min at 100 ℃, supernatant is centrifugally taken, and the supernatant is freeze-dried to prepare the yeast enzymolysis product freeze-dried powder.
Adding 60% (v/v) ethanol water solution into yeast enzymolysis product lyophilized powder, stirring, standing at 4deg.C for 12 hr, centrifuging at room temperature (2500 Xg, 20 min), concentrating supernatant at 55deg.C under reduced pressure to remove ethanol, and lyophilizing. Separating the lyophilized powder obtained by extracting with ethanol water solution with Sephadex Peptide 10/300GL chromatographic column, eluting with ultrapure water at flow rate of 0.5mL/min, detecting at 214nm detection wavelength, and collecting the 2 nd component F 2 (FIG. 1).
Identification of F by LC-MS/MS 2 Component, a tetrapeptide was found with the sequence tryptophan-proline-leucine-proline (Trp-Pro-Leu-Pro) derived from saccharomyces cerevisiae (Saccharomyces cerevisiae (strain ATCC 204508/S288 c)) alcohol dehydrogenase II, protein accession No.: p00331. The theoretical isoelectric point of the small molecule tetrapeptide is 3.70. The molecular weight of the small molecule polypeptide is 511.27g/mol.
Example 2
The tetrapeptides were prepared synthetically using Fmoc solid phase synthesis. According to the amino acid residue composition of tetrapeptides, taking various amino acids (Fmoc-Trp, fmoc-Pro and Fmoc-Leu) with fluorenylmethoxycarbonyl (Fmoc-) protecting groups at the amino end as raw materials, and connecting carboxyl groups of the Fmoc-Pro with a high polymer resin (Wang resin) through covalent bonds; adding 20% (v/v) piperidine Dimethylformamide (DMF), and reacting for 0.5h to remove amino protecting group Fmoc-; adding excessive Fmoc-Leu, taking Hydroxybenzotriazole (HOBT) as a condensing agent, and reacting for 2 hours at 30 ℃ to enable carboxyl of the Fmoc-Leu to be condensed with active amino of Pro on the resin; repeating deprotection and condensation reaction, sequentially connecting other residual amino acids, then cracking the tetrapeptide from the resin, separating and purifying by a C18 column, and freeze-drying to obtain the DPP-IV inhibitory tetrapeptide. The purity of the small molecule polypeptide of the invention synthesized by the method is 99.95% as shown by analysis of a liquid chromatogram (figure 2). The liquid chromatography-mass spectrometry (figure 3) proves that the synthesized polypeptide sequence is tryptophan-proline-leucine-proline (Trp-Pro-Leu-Pro).
Example 3
In a 96-well ELISA plate, 25. Mu.L of the sample and 50. Mu.L of DPP-IV enzyme solution (available from sigma Co., ltd.; cat# D3446) with a concentration of 200ng/mL were added, the mixture was incubated at 37℃for 10min, and finally 25. Mu.L of the substrate Gly-Pro-AMC (with a final concentration of 0.5 mmol/L) were added, and the ELISA plate was subjected to one fluorescence reading per minute in a kinetic mode, and the measurement was carried out for 15 to 30min (37 ℃, lambda.) ex =360/λ em =460 nm). 100mmol/L Tris-HCl buffer (pH 8.0) was used as a blank instead of DPP-IV enzyme solution, and the accepted DPP-IV inhibition tripeptide Diprotin A (IPI) was used as a positive control, 3 replicates per group.
For each well the data was plotted as "fluorescence value versus time", and two time points (T 1 And T 2 ) And its corresponding fluorescence value (FLU) 1 And FLU (flash memory Unit) 2 ) The slope of the image is thereby obtained. The calculation formula of the DPP-IV relative inhibition rate is shown below.
Wherein T is 1 And T 2 : two time points selected within the linear range of the graph; FLU (flash light unit) 1 And FLU (flash memory Unit) 2 : time T 1 And T 2 The corresponding fluorescence value; slope EC : slope of control group; slope SM : slope of the experimental group.
semi-Inhibitory Concentration (IC) 50 ) Is the concentration of the sample required when DPP-IV inhibition reaches 50%. Sample solutions with different concentrations are respectively prepared, DPP-IV inhibition rates are measured, the sample concentration is taken as an abscissa, the DPP-IV inhibition rate is taken as an ordinate, fitting is carried out through a nonlinear curve, and IC is calculated 50 Values.
As can be seen from FIG. 4, the tetrapeptides of the present invention inhibit DPP-IV at various concentrations, and their IC is calculated 50 The value was 178.90. Mu. Mol/L. The small molecule polypeptide has good DPP-IV inhibition activity and can be used for developing medicaments with blood sugar reducing function.
Example 4
In the DPP-IV inhibition activity experiment, the substrate Gly-Pro-AMC is respectively provided with different concentration gradients: 0.0625mmol/L, 0.0833mmol/L, 0.125mmol/L, 0.25mmol/L and 0.5mmol/L. The inhibition of DPP-IV by tetrapeptide WPLP at 100. Mu. Mol/L and 200. Mu. Mol/L was determined at different substrate concentrations. The Lineweaver-Burk double reciprocal plot (FIG. 5) shows that the type of inhibition of DPP-IV by polypeptide WPLP is an anti-competitive inhibition.
Example 5
Concentration-inhibition curves for sitagliptin and WPLP were plotted, yielding sitagliptin concentrations of 81nmol/L (30% inhibition concentration), 124nmol/L (50% inhibition concentration) and 196nmol/L (70% inhibition concentration) corresponding to Equivalent Doses (ED) of WPLP of 91. Mu. Mol/L, 177. Mu. Mol/L and 319. Mu. Mol/L, respectively.
The concentrations of sitagliptin were fixed at 81nmol/L, 124nmol/L and 196nmol/L, and then the DPP-IV inhibition ratios of the respective complex systems were determined by complex formulation with WPLPs of 25. Mu. Mol/L, 50. Mu. Mol/L, 100. Mu. Mol/L, 150. Mu. Mol/L, 200. Mu. Mol/L, 250. Mu. Mol/L and 300. Mu. Mol/L, respectively. And drawing a combined effect curve of sitagliptin and WPLP by taking the WPLP concentration as an abscissa and the DPP-IV inhibition rate of the compound system as an ordinate. The combined effect curve is compared with the base line (concentration of inhibitory polypeptide WPLP-inhibition curve), the combined effect curve is synergistic above the base line, antagonistic below, and additive. As a result, as shown in fig. 6, low-dose sitagliptin (30% inhibition) had some synergy with WPLP, while the combined inhibition of medium-high-dose sitagliptin (50% and 70% inhibition) with WPLP was shown to be additive.
Example 6
During the course of the investigation of the present invention, the process of the present invention was carried out by LC-MS/MS from example 1F 2 186 polypeptides were identified in the fractions. Several of these polypeptides were synthesized by solid phase synthesis and their DPP-IV inhibitory activity at a concentration of 0.40mmol/L was studied by the method of example 3, as shown in FIG. 7. The inhibitory activity of the tetrapeptide WPLP on DPP-IV is the best, the effect is obviously superior to other polypeptides, and the polypeptide DPP-IV has unexpected effect.
The embodiments described above are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the embodiments described above, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principles of the present invention should be made in the equivalent manner, and are included in the scope of the present invention.
Claims (10)
1. A tetrapeptide having DPP-IV inhibitory activity, characterized by: the amino acid sequence is tryptophan-proline-leucine-proline (Trp-Pro-Leu-Pro).
2. Use of a tetrapeptide having DPP-IV inhibitory activity as defined in claim 1 for the preparation of a medicament for the prevention and/or treatment of type ii diabetes.
3. Use of a tetrapeptide with DPP-IV inhibitory activity according to claim 1 in combination with sitagliptin for the preparation of a medicament for the prevention and/or treatment of type ii diabetes.
4. A use according to claim 3, characterized in that: the sitagliptin exists in a dosage of 75-85 mu mol/L.
5. A DPP-IV inhibitor, characterized in that: comprising the tetrapeptide of claim 1 having DPP-IV inhibitory activity.
6. The DPP-IV inhibitor according to claim 5, characterized in that: the DPP-IV inhibitor also contains sitagliptin.
7. The DPP-IV inhibitor according to claim 6, characterized in that: the sitagliptin exists in a dosage of 75-85 mu mol/L.
8. A hypoglycemic agent, characterized in that: comprising the tetrapeptide of claim 1 having DPP-IV inhibitory activity.
9. The hypoglycemic drug according to claim 8, wherein: the hypoglycemic medicine also contains sitagliptin.
10. The hypoglycemic drug according to claim 9, wherein: the sitagliptin exists in a dosage of 75-85 mu mol/L.
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RU2011134582A (en) * | 2011-08-18 | 2013-03-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") | INHIBITING DIPEPTIDYLPEPTIDASE IV MEANS AND PHARMACEUTICAL COMPOSITION ON ITS BASIS |
JP2015084694A (en) * | 2013-10-29 | 2015-05-07 | 森永乳業株式会社 | Dipeptidyl peptidase-iv inhibitors |
CN106554388A (en) * | 2015-09-25 | 2017-04-05 | 中国科学院大连化学物理研究所 | Polypeptide with ACE and DPP-IV inhibitory activity and its application |
CN110845575A (en) * | 2018-07-27 | 2020-02-28 | 中国科学院大连化学物理研究所 | Polypeptide and application thereof as well as DPP-IV inhibitor or hypoglycemic drug |
CN112442108A (en) * | 2019-08-29 | 2021-03-05 | 中国科学院大连化学物理研究所 | ACE and DPP-IV inhibitory peptide of medlar, derivative polypeptide, application and mixture |
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RU2011134582A (en) * | 2011-08-18 | 2013-03-10 | Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") | INHIBITING DIPEPTIDYLPEPTIDASE IV MEANS AND PHARMACEUTICAL COMPOSITION ON ITS BASIS |
JP2015084694A (en) * | 2013-10-29 | 2015-05-07 | 森永乳業株式会社 | Dipeptidyl peptidase-iv inhibitors |
CN106554388A (en) * | 2015-09-25 | 2017-04-05 | 中国科学院大连化学物理研究所 | Polypeptide with ACE and DPP-IV inhibitory activity and its application |
CN110845575A (en) * | 2018-07-27 | 2020-02-28 | 中国科学院大连化学物理研究所 | Polypeptide and application thereof as well as DPP-IV inhibitor or hypoglycemic drug |
CN112442108A (en) * | 2019-08-29 | 2021-03-05 | 中国科学院大连化学物理研究所 | ACE and DPP-IV inhibitory peptide of medlar, derivative polypeptide, application and mixture |
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