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Stable polypeptide protein targeted inhibitor and application thereof

A polypeptide and protein target technology, applied in the field of bioengineering, can solve problems such as poor breast cancer effect, achieve significant technological progress, inhibit growth, and broaden the application range

Active Publication Date: 2021-05-14
PEKING UNIV SHENZHEN GRADUATE SCHOOL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a stable polypeptide protein targeting inhibitor and its use. The stable polypeptide protein targeting inhibitor and its use should solve the problems in the prior art. The technical problem that the drug is not effective in the treatment of breast cancer

Method used

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  • Stable polypeptide protein targeted inhibitor and application thereof
  • Stable polypeptide protein targeted inhibitor and application thereof
  • Stable polypeptide protein targeted inhibitor and application thereof

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Effect test

Embodiment 1

[0034]In order to better carry out the following research, the design of the control peptide is necessary. As shown in Table 1, we designed a series of control peptides. The present invention selects the SAH-p53-8 sequence (Ac-Q-S-Q-Q-T-F-*-N-X-W-R-L-L-#-Q-N-NH2) as the original sequence, and replaces it with methionine at the X site. And combined with the research strategy of Professor Wang Lei's research group (L. Wang, Chem. Commun., 2016, 52, 5140), they replaced the 22-position leucine in the SAH-p53-8 sequence with an aromatic group-containing Sulfonyl fluoride compound, which increases the inhibitory effect of SAH-p53-8 by 10 times. In the present invention, lysine and aspartic acid are used for side chain closure at position i and position i+7, thereby further stabilizing the polypeptide. The synthesized polypeptide (1equiv.) was reacted with propyne bromide reagent (5equiv.) under acidic conditions for 12 hours to construct the polypeptides in Table 1. The present ...

Embodiment 2

[0037] Preparation and separation and purification steps of the polypeptide of embodiment 2:

[0038] According to the amino acid sequence of solid-phase synthesis of polypeptides, the core steps for preparing the above-mentioned stable polypeptides are as follows (taking Peptide-2 as an example):

[0039]

[0040] The specific operation steps are:

[0041] (1) Polypeptide solid-phase synthesis: Weigh 100 mg Rink amide MBHA resin into a 10 ml peptide tube, add dichloromethane (DCM), and swell with nitrogen gas for 30 min. Add 50% (v / v) morpholine in N,N-dimethylformamide (DMF) solution, blow nitrogen gas for 30 minutes, and remove the Fmoc protecting group. After washing the resin 6 times alternately with DMF and DCM, the prepared (1) Fmoc-Asn-OH (5eq, 0.4M, DMF) solution, 6-chlorobenzotriazole-1,1,3,3-tetramethyl Urea hexafluorophosphate (HCTU) (5eq, 0.38M, DMF) solution and N,N-diisopropylethylamine (DIPEA) (10eq) were mixed well, then added to the resin and blown with ...

Embodiment 3

[0047] The experiment of embodiment 3 sulfonium salt-alkyne and lysine reaction

[0048] The present invention designs a model reaction, selects propargyl dimethyl sulfonium salt and Boc-Lys-OH as substrates to react in water for 12 hours, and then purifies by HPLC to obtain the target product. The present invention has carried out careful nuclear magnetic resonance (NMR) experiments, including 1H NMR, 13C{1H} NMR, heteronuclear single quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC) and total correlation spectroscopy (TOCSY), It can be confirmed that propargyl sulfonium salts can react with amino groups on lysine (such as Figure 4 ). Figure 4 A: 1H NMR: 1 H NMR (400MHz DMSO-d6) δ7.85–7.32(m,1H),6.29(d,J=7.5Hz,1H),4.39(s,1H),3.90–3.57(m,1H),2.83(s ,7H),2.05(s,3H),1.34(m,17H); Figure 4 B: 13 C{ 1 H}NMR: 13 C{ 1 H}NMR(400MHz DMSO-d6)δ174.7,158.6,158.5,158.2,155.3,118.8,115.8,77.6,69.1,54.6,52.0,44.9,42.9,31.9,31.5,28.3,27.1,23.1,18.1,8.8,7.7 ;...

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PUM

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Abstract

The invention provides a stable polypeptide protein targeted inhibitor, the amino acid sequence of the stable polypeptide protein targeted inhibitor is as shown in the specification: Ac-Q-S-Q-Q-F-K-N-Mq-W-R-L-L-D-Q-N-NH2, and Mq is as shown in the specification. The invention also provides application of the stable polypeptide protein targeted inhibitor in preparation of drugs for inhibiting MDM4 protein. Nuclear magnetism, secondary mass spectrometry and the like prove that polypeptide disclosed by the invention can be covalently bound with lysine on the MDM4 protein, so that the binding activity of the MDM4 protein and the p53 protein is influenced. Meanwhile, cell proliferation experiments also prove that the polypeptide can inhibit proliferation of breast cancer cells.

Description

technical field [0001] The invention belongs to the field of bioengineering and relates to a polypeptide, in particular to a stable polypeptide protein targeting inhibitor and its application. Background technique [0002] Among the currently known human tumor genes, p53, as a tumor suppressor gene, plays a very important role in the stability of cells and the maintenance of microenvironment, so it is also called "genome guard". When the intracellular environment in the body is damaged, such as DNA damage, etc., the transcription factor p53 will regulate the relevant genes accordingly, so that they can be expressed to promote the repair of cells. p53 plays a vital role in preventing cell malignant transformation. Currently, in human tumors, nearly 50% of tumors are found to be due to p53 gene mutation or inactivation, which makes p53 protein unable to perform normal functions. It can be further proved that p53 has a protective effect on the normal operation of life activiti...

Claims

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Application Information

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IPC IPC(8): C07K7/08A61K38/10A61P35/00A61P15/14
CPCC07K7/08A61P35/00A61P15/14A61K38/00
Inventor 李子刚尹丰王蕊廉晨珊李洋
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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