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A kind of stable polypeptide protein targeting inhibitor and use thereof

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

Active Publication Date: 2022-07-05
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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  • A kind of stable polypeptide protein targeting inhibitor and use thereof
  • A kind of stable polypeptide protein targeting inhibitor and use thereof
  • A kind of stable polypeptide protein targeting inhibitor and use thereof

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Experimental program
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Embodiment 1

[0034]In order to better carry out the following research, the design of control peptides is necessary. As shown in Table 1, we designed a series of control peptides. The present invention selects 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 its X position. And combined with the research strategy of Professor Wang Lei's research group (L. Wang, Chem. Commun., 2016, 52, 5140), they replaced the leucine at position 22 in the SAH-p53-8 sequence with an aromatic group containing leucine. The sulfonyl fluoride compound increased the inhibitory effect of SAH-p53-8 by 10 times. In the present invention, lysine and aspartic acid are used to close the side chain at the i position and the i+7 position, so that the polypeptide can be further stabilized. The synthesized polypeptide (1 equiv.) was reacted with bromopropyne reagent (5 equiv.) under acidic conditions for 12 hours to construct the polypeptides in Ta...

Embodiment 2

[0037] The preparation of embodiment 2 polypeptide and separation and purification steps:

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

[0039]

[0040] The specific operation steps are:

[0041] (1) Polypeptide solid-phase synthesis: Weigh 100 mg of Rink amide MBHA resin into a 10 ml peptide tube, add dichloromethane (DCM), and swell with nitrogen for 30 min. A 50% (v / v) solution of morpholine in N,N-dimethylformamide (DMF) was added, and nitrogen was bubbled for 30 min to remove the Fmoc protecting group. After alternately washing the resin 6 times 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, N,N-diisopropylethylamine (DIPEA) (10eq) were mixed, and then added to the resin with nitrogen...

Embodiment 3

[0047] Example 3 Experiment of 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 inventors 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 (e.g. 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 ; Figure 4 C: ...

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Abstract

The present invention provides a stable polypeptide protein targeting inhibitor, the amino acid sequence of which is as follows: Ac-Q-S-Q-Q-F-K-N-M q ‑W‑R‑L‑L‑D‑Q‑N‑NH 2 , where M q The present invention also provides the use of the above-mentioned stable polypeptide protein targeting inhibitor in preparation for inhibiting MDM4 protein. It is proved by nuclear magnetic resonance and secondary mass spectrometry that the polypeptide of the present invention can covalently bind to lysine on MDM4 protein, thereby affecting the binding activity of MDM4 protein and p53 protein. At the same time, the cell proliferation experiment also proved that the polypeptide of the present invention can inhibit the 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 use thereof. 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 the microenvironment, so it is also known as the "guardian of the genome". When the intracellular environment in the body is damaged, such as DNA damage, the transcription factor p53 will regulate related genes accordingly, so that it can be expressed to promote cell repair. p53 plays a crucial role in preventing malignant transformation of cells. Currently, in human tumors, nearly 50% of tumors are found to be due to the mutation or inactivation of the p53 gene, which makes the p53 protein unable to function normally. It can be further proved that p53 has a protective effect on the normal operation of life...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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