CN114437177A - PUMABH3 mimic peptide compound with PTP1B as target, and preparation method and application thereof - Google Patents
PUMABH3 mimic peptide compound with PTP1B as target, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a PUMABH3 mimic peptide compound taking PTP1B as a target spot, and a preparation method and application thereof, wherein the structural formula of the PUMABH3 mimic peptide compound is as follows:the structure of the said PUMABH3 mimic peptide compoundThe amino acids are all natural amino acids, and the amino terminal and R of the peptide chain1The radicals being linked by amide bonds, R1Is a carboxylic or dicarboxylic acid, R2Is OH or NH2. The mimic peptide compound is derived from the core region of the BH3 structural domain of Bcl-2 anti-apoptosis protein and is prepared by a polypeptide solid phase synthesis method. Experiments prove that the PUMABH3 mimic peptide compound can obviously inhibit the activity of protein tyrosine phosphorylase 1B (PTP1B), and has potential application value in the development of medicaments for relevant diseases taking PTP1B as a target, such as diabetes, cancer, Alzheimer's disease and the like.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a PUMABH3 analog compound taking PTP1B as a target spot, and a preparation method and application thereof.
Background
Protein tyrosine phosphatase 1B (PTP1B) was successfully isolated and identified as early as 1988, and subsequent numerous research results show that the excessive abnormal expression of PTP1B is closely related to the onset and development of T2DM obesity. PTP1B is a novel potential target for the treatment of T2DM and obesity. PTP1B is a key negative regulator in an insulin signal transduction pathway, and a PTP1B inhibitor influences phosphorylation of an insulin receptor substrate (IRS-1) by blocking tyrosine phosphorylation of an Insulin Receptor (IR) stimulated by insulin, so that insulin-like and insulin are sensitized, insulin resistance effect is improved, and blood sugar is reduced. Meanwhile, leptin signals can be enhanced, fat metabolism level is increased, and body weight is reduced. By inhibiting the activity of PTP1B, the insulin sensitivity can be enhanced, the insulin resistance of a T2DM patient can be effectively improved, and the treatment of T2DM and obesity can be obviously improved from the source. PTP1B is considered one of the most ideal targets for development of non-insulin dependent anti-type 2 diabetes and obesity drugs. Therefore, the search and development of PTP1B inhibitor with high specificity and low toxicity has wide application prospect. Numerous pharmaceutical companies such as feverfew, ISIS, tabaco, TransTech, etc. have been attracted to develop specific, highly potent inhibitors thereof as new drugs for T2DM and obesity treatment. In China, a plurality of scientific research institutes (such as the institute of medicine of Chinese academy of sciences, the institute of oceanography of Chinese academy of sciences, Shanghai university of transportation, Zhejiang university, Jilin university, China eastern science university, south China Kao university, Compound denier university, China medical university, Zhongshan university and the like) are developing basic theories and application researches of PTP1B inhibitors, so that the PTP1B inhibitor becomes a very active field in the development of blood sugar-reducing medicines. Multiple candidate compounds such as Ertiprostafib, TTP814, ISIS-PTPRx, ISIS-113715, MSI-1436, HPN, etc. were sequentially introduced into preclinical and clinical phase I, II experiments.
Furthermore, recent studies have shown that: PTP1B can be a (potential) target for the development of anti-tumor and alzheimer drugs. The literature Protein tyrosine phosphatases, new Targets for cancer therapy, curr. cancer Drug Targets 2006,6, 519-532; a break belonges an accumulator, PTP1B-a new therapeutic target for break accumulator, cancer Cell 2007,11,214 and 216; discovery of [ (3-bromo-7-cyano-2-naphthyl) (difluoro) methyl ] -phosphonic acid, a locus and organism active small molecule PTP1B inhibitor, bioorg, Med. chem. Lett.2008,18, 3200. 3205; recent advances in the discovery of reactive protein type phosphorus 1B Inhibitors for the treatment of diabetes, obesity, and cancer. J Med Chem,53(6) (2010), pp. 2333-2344; PTP1B control non-mitochondrial oxygen control by regulating RNF213 to promoter tulour Survival duringhypoxia. nat Cell Biol,18(2016), p.803. etc. research finds that PTP1B overexpression can remarkably promote the generation and growth of tumors in mice, and can generate an anti-tumor effect through the inhibitor expression of PTP 1B; the mechanism research finds that PTP1B controls the non-mitochondrial oxygen consumption of cells by regulating RNF213 gene, thereby promoting the survival and growth of tumor cells under the anoxic condition. Thus, PTP1B is considered a target for anti-tumor drugs. In the patent of Protein tyrosine phosphatase 1B (PTP1B), a potential target for Alzheimer's therapy front Aging Neurosci,9(7) (2017) summarizes the regulation effect of PTP1B in recent years as the physiological process related to Alzheimer's disease in the central nervous system, and proposes a strategy for antagonizing the harmful physiological process related to Alzheimer's disease regulated by PTP1B by inhibiting PTP1B, so as to research and develop the anti-Alzheimer's disease medicine.
Therefore, PTP1B has become a hot target for development of anti-diabetic, cancer and Alzheimer's disease drugs. The inhibitors of PTP1B that have been found to date can be divided mainly into three classes: the first is an inorganic small molecule compound represented by sodium vanadate, which has a similar structure with a substrate phosphate of PTP1B, and can competitively bind to PTP1B and inhibit the activity thereof. But the selectivity is very low, and the compounds have strong inhibition on all PTPs, so the compounds have no development prospect and cannot be applied to clinical treatment. The second type is organic compounds, most of the substances are screened by organic synthesis and combinatorial chemistry methods, compounds with PTP1B activity inhibition are screened firstly, then substituent groups of the compounds are modified, and finally a better PTP1B inhibitor is obtained. However, the inhibitors have the problems of poor stability, high charge, high lipophilic coefficient and the like which restrict the drug property. Although there are several inhibitors with relatively good selectivity, these PTP1B inhibitors also have inhibitory effects on the TCPTP with the highest homology of PTP1B, and thus, the search for highly specific, highly potent, and low-toxic PTP1B inhibitors remains a great challenge. In recent years, researchers at home and abroad aim at researching and developing a PTP1B inhibitor of a third class, namely a PTP1B inhibitor in natural products. By high-throughput screening of natural products isolated and identified in nature, PTP1B inhibitors with some action sites not very clear but high selectivity and activity are obtained. Such natural products are structurally modified and engineered based on their parent nuclear structure, binding to the catalytically active site of the PTP1B enzyme. Thus, a PTP1B inhibitor which is highly selective, low-toxic and highly effective is developed.
Summarizing and analyzing the current development of small organic molecule inhibitors of PTP1B, it can be found that the development of small molecule inhibitors of PTP1B is limited to two points: (ii) selectivity of PTP1B inhibitor: PTP1B is highly homologous to other protein phosphatases such as TCPTP, especially with an active site homology as high as 94%; (ii) membrane permeability of PTP1B inhibitor: PTP1B catalyzes the hydrolysis of protein phosphate to obtain charged active sites, so compounds with PTP1B inhibitory activity are charged or strongly polar; PTP1B is distributed in cell membranes, and charged or strongly polar compounds are difficult to pass through to take effect. Therefore, it is necessary to make up for the defects of the existing PTP1B inhibitory molecules and develop a novel PTP1B inhibitor with novel structure and strong selectivity so as to meet the urgent needs of domestic clinical application. The key point is to discover a new lead structure and an action mode, and the research is also a hot spot in the basic research aspect of the current PTP 1B.
Disclosure of Invention
The invention aims to provide a PUMABH3 mimic peptide compound taking PTP1B as a target spot, and a preparation method and application thereof, and the PUMABH3 mimic peptide compound provided by the invention has obvious inhibition activity of protein tyrosine phospholipase 1B (PTP1B), and can be used for preparing and developing drugs for preventing or treating related diseases taking PTP1B as a target spot.
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
the invention provides a PUMABH3 mimic peptide compound taking PTP1B as a target, wherein the mimic peptide compound has the following structural formula:
wherein R is1Is a carboxylic or dicarboxylic acid, R2Is OH or NH2。
Further: the amino acids in the PUMABH3 mimic peptide compound are all natural amino acids, and the amino terminal and R of a peptide chain1The groups are linked by amide bonds.
Further: the PUMABH3 mimic peptide compound is specifically as follows:
the invention also provides a preparation method of the PUMABH3 mimic peptide compound, which comprises the following steps:
(1) resin activation: weighing corresponding amount of Fmoc-Phe-Wang resin at room temperature, placing the Fmoc-Phe-Wang resin in a manual polypeptide solid phase synthesizer, and activating;
(2) adding mixed solution of piperidine and dimethylformamide to remove the Fmoc protecting group;
(3) adding N-Fmoc protected amino acid, HOBt, HBTU and DIEA in an amount which is 3-4 times the molar weight of the resin, and oscillating at room temperature for 2-4 hours;
(4) repeating steps (2) and (3) until the synthesis of the whole polypeptide sequence is completed;
(5) draining the resin, adding a lysis solution, oscillating by a shaking table, filtering, blowing nitrogen to remove residual trifluoroacetic acid, adding ether, separating out a solid, centrifuging and drying to obtain a crude mimetic peptide compound;
(6) and purifying the crude product by using a reversed-phase preparative liquid chromatography, collecting a target peak mobile phase solution, removing acetonitrile, and freeze-drying to obtain a pure product of the mimic peptide compound.
Further: the cracking liquid comprises phenol, water, thioanisole and trifluoroacetic acid.
The invention also provides a medicament or a pharmaceutical composition taking the PUMABH3 mimic peptide compound as an active ingredient, which comprises any one of the PUMABH3 mimic peptide compound and one or more pharmaceutically acceptable carriers or excipients.
The invention also provides application of the PUMABH3 mimic peptide compound in preparation of a medicament for preventing or treating diseases taking PTP1B as a target.
Further: the diseases include diabetes, cancer and alzheimer's disease.
Further: the medicine or the pharmaceutical composition taking the PUMABH3 mimic peptide compound as an active ingredient is administrated by oral administration or injection.
The invention has the advantages and technical effects that: the invention provides a PUMABH3 mimic peptide compound taking PTP1B as a target spot, a preparation method and application thereof, wherein the PUMABH3 mimic peptide compound can obviously inhibit the activity of protein tyrosine phosphorylase 1B (PTP1B), has potential application value in the development of drugs for related diseases taking PTP1B as the target spot, such as diabetes, cancer, Alzheimer's disease and the like, and has excellent development prospect of PTP1B inhibitors.
Drawings
FIG. 1 is a graph of the inhibition rate of PTP1B by the peptidomimetic compound Pal-PUMA at different concentration gradients;
FIG. 2 is a graph of PTP1B inhibition rate of a peptidomimetic compound Pal-BID at various concentration gradients;
FIG. 3 is a graph of PTP1B inhibition rate of a peptidomimetic compound Pal-BAK at various concentration gradients;
FIG. 4 is a graph of the inhibition rate of PTP1B for the peptidomimetic compound Pal-BIK at various concentration gradients.
The specific implementation mode is as follows:
the technical solution of the present invention will be described in further detail with reference to specific examples.
The BH3 mimic peptide compound taking PTP1B as a target point is obtained according to a polypeptide solid phase synthesis method.
Example 1
1. The specific preparation process of Pal-PUMA is as follows:
(1) resin activation: weighing corresponding amount of Fmoc-Phe-Wang resin and Dichloromethane (DCM) for 4 times at room temperature, placing the resin in a manual polypeptide solid phase synthesizer, adding 5ml of DCM for swelling and activating for 3h, washing 4 times with Dimethylformamide (DMF), adding 20% piperidine DMF for removing Fmoc protecting groups for 20min, washing 4 times with 5ml of DMF, washing 4 times with 5ml of DCM, and detecting with Kaiser's reagent.
(2) To Leu (L): washing with DMF for 3 times, respectively adding Fmoc-Leu-OH, HBTU, HOBt and DIEA with the molar weight of 3 times of the resin and 6 times of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(3) To Asp (D): washing with DMF for 3 times, adding Fmoc-Asp (OtBu) -OH, HBTU, HOBt and DIEA with resin molar amount of 3 times and 6 times respectively, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(4) To Asp (D): washing with DMF for 3 times, adding Fmoc-Asp (OtBu) -OH, HBTU, HOBt and DIEA with resin molar amount of 3 times and 6 times respectively, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(5) Connection to Ala (A): washing with DMF for 3 times, respectively adding Fmoc-Ala-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(6) To Met (M): washing with DMF for 3 times, respectively adding Fmoc-Met-OH, HBTU, HOBt and DIEA with the molar weight of 3 times of the resin and 6 times of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(7) To Arg (R): washing with DMF for 3 times, respectively adding Fmoc-Arg (mtr) -OH, HBTU, HOBt and DIEA with 3 times of resin molar weight, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(8) To Arg (R): washing with DMF for 3 times, respectively adding Fmoc-Arg (mtr) -OH, HBTU, HOBt and DIEA with 3 times of resin molar weight, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(9) To Leu (L): washing with DMF for 3 times, respectively adding Fmoc-Leu-OH, HBTU, HOBt and DIEA with the molar weight of 3 times of the resin and 6 times of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(10) To Glu (Q): washing with DMF for 3 times, respectively adding Fmoc-Glu (OtBu) -OH, HBTU, HOBt and DIEA with the resin molar weight of 3 times and 6 times, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(11) Connection to Ala (A): washing with DMF for 3 times, respectively adding Fmoc-Ala-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(12) To Gly (G): washing with DMF for 3 times, respectively adding Fmoc-Gly-OH, HBTU, HOBt and DIEA with the molar weight of 3 times and 6 times of the resin molar weight, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml of DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(13) The connection Ile (I): washing with DMF for 3 times, respectively adding Fmoc-Ile-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups for 20min, washing with 5ml DMF for 4 times, washing with DCM for 4 times, and detecting with Kaiser's reagent.
(14) Ligation palmitic acid (Pal): washing with DMF for 3 times, respectively adding palmitic acid, HBTU, HOBt and DIEA with the molar weight being 6 times that of the resin and 10 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 4h, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(15) Cleavage, side chain protecting group cleavage: the product is drained, lysate (the lysate comprises 250mg phenol, 0.5ml water, 0.5ml thioanisole and 9.0ml trifluoroacetic acid) is added, the mixture is stirred for 2.5h at room temperature and filtered, and N is added2The trifluoroacetic acid was purged, 30ml of cold anhydrous ether was added, centrifugation was carried out at 5000rpm for 5 minutes to obtain a white precipitate, washing was repeated 3 times with cold anhydrous ether, and vacuum drying was carried out to obtain a crude product.
(16) Purifying the crude product by using reversed phase preparative liquid chromatography (RP-HPLC), collecting a target peak mobile phase solution, removing acetonitrile, freezing and drying to obtain a white solid, namely a pure BH3 mimic peptide compound, and carrying out structure confirmation by mass spectrometry and high performance liquid chromatography analysis.
Example 2
Mass spectral data and HPLC purity analysis data for the 8 BH3 mimetic compounds are shown in table 1.
TABLE 1 Mass Spectrometry data and HPLC purity analysis data for BH3 mimetics
Example 3 determination of the inhibitory Activity of protein tyrosine phospholipase 1B (PTP1B)
According to the invention, MES buffer solution is adopted as a reaction system, human protein tyrosine phosphatase 1B (PTP1B) is utilized, sodium paranitrophenylphosphate (pNPP) is taken as a specific substrate, sodium orthovanadate is taken as a positive drug, DMSO is taken as a negative control, a screening model with a 96-well microplate based on an enzyme reaction rate as a carrier is established, and a PTP1B inhibitor is searched by an enzymology method.
The specific implementation method comprises the following steps: mu.L of 10. mu.L of pNPP (77mM), 86. mu.L of MES buffer, 4. mu.L of compound (2mM compound stock solution in DMSO), and 100. mu.L of PTP1B solution (50nM) were sequentially added to a 96-well plate using MES buffer (25mM, pH6.5) in a total reaction volume of 200. mu.L. Each group of 3 replicates were shaken at 25 ℃ for 1min on a shaker with DMSO as a negative control and sodium orthovanadate (2mM) as a positive control, read every 60s on a microplate reader, and dynamically measured for 5min to determine the change in OD 405 (OD/min). The initial phase reaction rates for each well are linearly related and the slope of the linear portion of the kinetic curve determines the reaction rate of PTP1B, which is indicative of enzyme activity. The inhibition rate of the compound on PTP1B is calculated according to the formula:
inhibition (%) - (vmdmso-v sample)/vmdmso x 100;
the vDMSO, v samples represent the initial average reaction rates of the negative control group and test compound, respectively.
For the obtained dataIndicating that each group of data was analyzed using t-test. The results are shown in Table 2.
TABLE 2 results of inhibition of PTP1B activity by test mimetic peptides
The invention performs PTP1B inhibition rate and IC on the simulated peptide compounds Pal-PUMA, Pal-BID, Pal-BAK and Pal-BIK under different concentration gradients50The results of the measurements are shown in Table 3 and FIGS. 1 to 4.
TABLE 3 inhibition of PTP1B Activity by Polypeptides at different concentration gradients and IC50
Performing statistical treatment by using GraphPad Prism 5.0 software, drawing an inhibition rate curve as shown in fig. 1 to 4, thereby obtaining the concentration IC in PTP1B inhibition of simulated peptide compounds Pal-PUMA, Pal-BID, Pal-BAK and Pal-BIK50Respectively 6.84. mu. mol/L, 2.15. mu. mol/L, 1.28. mu. mol/L and 0.94. mu. mol/L.
The test result shows that: the mimic peptide compounds Pal-PUMA, Pal-BID, Pal-BAK and Pal-BIK show obvious inhibition effect on protein tyrosine phosphatase 1B, and have excellent development prospect of PTP1B inhibitor.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing examples, it will be apparent to those skilled in the art that various changes in the embodiments and modifications can be made, and equivalents can be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (9)
2. The pumalbh 3 peptidomimetic compound of claim 1, wherein: the amino acids in the PUMABH3 mimic peptide compound are all natural amino acids, and the amino terminal and R of a peptide chain1The groups are linked by amide bonds.
4. the process for preparing a pamab 3 peptidomimetic compound of claim 1, wherein: it comprises the following steps:
(1) resin activation: weighing corresponding amount of Fmoc-Phe-Wang resin at room temperature, placing the Fmoc-Phe-Wang resin in a manual polypeptide solid phase synthesizer, and activating;
(2) adding mixed solution of piperidine and dimethylformamide to remove the Fmoc protecting group;
(3) adding N-Fmoc protected amino acid, HOBt, HBTU and DIEA in an amount which is 3-4 times the molar weight of the resin, and oscillating at room temperature for 2-4 hours;
(4) repeating steps (2) and (3) until the synthesis of the whole polypeptide sequence is completed;
(5) draining the resin, adding a lysis solution, oscillating by a shaking table, filtering, blowing nitrogen to remove residual trifluoroacetic acid, adding ether, separating out a solid, centrifuging and drying to obtain a crude mimic peptide compound;
(6) and purifying the crude product by using a reversed-phase preparative liquid chromatography, collecting a target peak mobile phase solution, removing acetonitrile, and freeze-drying to obtain a pure product of the mimic peptide compound.
5. The method of claim 4 for the preparation of a pamab 3 peptidomimetic compound, wherein the steps of: the cracking liquid comprises phenol, water, thioanisole and trifluoroacetic acid.
6. A pharmaceutical or pharmaceutical composition comprising as an active ingredient a pamab 3 peptidomimetic compound according to any one of claims 1 to 3, comprising any one of said pamab 3 peptidomimetic compounds and one or more pharmaceutically acceptable carriers or excipients.
7. Use of a pambh 3 mimetic peptide compound according to any one of claims 1-3 for the preparation of a medicament for the prevention or treatment of PTP 1B-targeted diseases.
8. The use of a pamab 3 peptidomimetic compound according to claim 7 for the preparation of a medicament for the prevention or treatment of diseases targeting PTP1B, wherein: the diseases include diabetes, cancer and alzheimer's disease.
9. The use of a pamab 3 peptidomimetic compound according to claim 7 for the preparation of a medicament for the prevention or treatment of diseases targeting PTP1B, wherein: the medicine or the pharmaceutical composition taking the PUMABH3 mimic peptide compound as an active ingredient is administrated by oral administration or injection.
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CN202210040747.4A Active CN114437178B (en) | 2018-12-12 | 2018-12-12 | BIDBH3 mimic peptide compound taking PTP1B as target point, and preparation method and application thereof |
CN202210040752.5A Active CN114409739B (en) | 2018-12-12 | 2018-12-12 | BIKBH3 mimic peptide compound taking PTP1B as target point, and preparation method and application thereof |
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