Novel BH3 analog peptide compound taking PTP1B (Protein Tyrosine Phosphatase 1B) as target spot as well as preparation method and application thereof

A technology of compounds and mimetic peptides, which is applied in the field of new BH3 mimetic compounds and their preparation, can solve problems such as compound difficulty and achieve excellent development prospects

Active Publication Date: 2019-04-05
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Summarizing and analyzing the development status of PTP1B organic small molecule inhibitors, it can be found that the development of PTP1B small molecule inhibitors suffers from two points: ① The selectivity of PTP1B inhibitors: PTP1B is highly homologous to other protein phosphatases such as TCPTP, especially the activity The site homology is as high as 94%; ②PTP1B inhibitor membrane penetration ability: PTP1B catalyzes protein phosphorylation and the active site is charged, so compounds with PTP1B inhibitory activity are charged or strongly polar; and PTP1B is distributed in the cell membrane Intrinsic, charged or highly polar compounds have difficulty crossing cell membranes to act

Method used

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  • Novel BH3 analog peptide compound taking PTP1B (Protein Tyrosine Phosphatase 1B) as target spot as well as preparation method and application thereof
  • Novel BH3 analog peptide compound taking PTP1B (Protein Tyrosine Phosphatase 1B) as target spot as well as preparation method and application thereof
  • Novel BH3 analog peptide compound taking PTP1B (Protein Tyrosine Phosphatase 1B) as target spot as well as preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0035] 1. The specific preparation process of Pal-PUMA is as follows:

[0036] (1) Resin activation: at room temperature, weigh the corresponding amount of Fmoc-Phe-Wang resin, wash it with dichloromethane (DCM) 4 times, place it in a manual polypeptide solid-phase synthesizer, add 5ml DCM to swell and activate it for 3 hours, and dimethicone Washed 4 times with methyl formamide (DMF), added 20% piperidine DMF to remove the Fmoc protecting group for 20 min, washed 4 times with 5ml DMF, washed 4 times with 5ml DCM, and tested with Kaiser's reagent.

[0037] (2) Connecting Leu(L): DMF was washed 3 times, Fmoc-Leu-OH, HBTU, HOBt and 6 times the resin molar weight of DIEA were added respectively, dissolved in 10ml DMF, stirred at room temperature for 2 hours , washed 4 times with DMF, added 20% piperidine DMF to remove the Fmoc protecting group for 20 min, washed 4 times with 5ml DMF, washed 4 times with 5ml DCM, and detected by Kaiser's reagent.

[0038] (3) Asp(D) connection: w...

Embodiment 2

[0053] The mass spectrum data and HPLC purity analysis data of the eight BH3 mimetic peptide compounds are shown in Table 1.

[0054] Table 1. Mass Spectrometry Data and HPLC Purity Analysis Data of BH3 Mimetic Peptides

[0055]

Embodiment 3

[0056] Example 3, Determination of protein tyrosine phospholipase 1B (PTP1B) inhibitory activity

[0057] In the present invention, MES buffer is adopted as reaction system, human protein tyrosine phosphatase 1B (PTP1B) is utilized, disodium p-nitrophenylphosphate (pNPP) is used as specific substrate, and sodium orthovanadate is selected as positive drug , With DMSO as negative control, a screening model based on enzyme reaction rate of 96-well microplate as carrier was established, and PTP1B inhibitors were found by enzymatic methods.

[0058] The specific implementation method is: using MES buffer system (25mM, pH6.5), sequentially add 10μL pNPP (77mM), 86μL MES buffer, 4μL compound (2mM compound mother solution dissolved in DMSO), 100μL PTP1B solution ( 50 nM), the total reaction volume was 200 μL. 3 parallels in each group, with DMSO as the negative control and sodium orthovanadate (2mM) as the positive control, at 25°C, shake on the shaker for 1min, read on the microplat...

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Abstract

The invention provides a novel BH3 analog peptide compound taking PTP1B (Protein Tyrosine Phosphatase 1B) as a target spot as well as a preparation method and application thereof. A structural formulaof the novel BH3 analog peptide compound is as shown in the description; in the structure of the novel BH3 analog peptide compound, amino acids are all natural amino acids, an amino terminal of a peptide chain is connected with an R1 group through an amido bond, R1 is carboxylic acid or dicarboxylic acid, and R2 is OH or NH2. The novel BH3 analog peptide compound provided by the invention is derived from a core region of a BH3 structural domain of Bcl-2 anti-apoptotic protein and is prepared by adopting a polypeptide solid-phase synthesis method. According to the novel BH3 analog peptide compound provided by the invention, an experiment verifies that the novel BH3 analog peptide compound is capable of remarkably inhibiting the activity of the protein tyrosine phosphatase 1B (PTP1B), and has potential application value in development of drugs, which take the PTP1B as the target spot, for related diseases, such as diabetes, cancer and Alzheimer's disease.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a novel BH3 mimetic compound targeting PTP1B and its preparation method and application. Background technique [0002] Protein tyrosine phosphatase 1B (protein tyrosine phosphatase 1B, PTP1B) was successfully isolated and identified as early as 1988. A large number of follow-up research results have shown that the excessive and 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 regulatory protein in the insulin signal transduction pathway. PTP1B inhibitors block the insulin-stimulated insulin receptor (IR) tyrosine phosphorylation, thereby affecting the insulin receptor substrate (IRS-1) Phosphorylation, insulin-like and insulin-sensitizing, improving insulin resistance, lowering blood sugar. At the same time, it can enhance the sign...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K1/08C07K1/06C07K1/20A61K38/10A61P35/00A61P25/28A61P3/10
CPCA61P3/10A61P25/28A61P35/00C07K7/08A61K38/00Y02P20/55
Inventor 张传亮王树林路晓吴丽娟
Owner OCEAN UNIV OF CHINA
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