A kind of α-helical polypeptide inhibitor targeting hras protein and its use

A polypeptide inhibitor and α-helix technology, which is applied in the field of α-helix polypeptide inhibitors, can solve the problems of weak cell membrane penetration and low binding affinity, and achieve the effects of increasing radiation sensitivity, solving resistance, and broadening the scope of application

Active Publication Date: 2022-05-10
PEKING UNIV SHENZHEN GRADUATE SCHOOL +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the above-mentioned technical problems in the prior art, the present invention provides an α-helical polypeptide inhibitor targeting HRas protein and its application. The α-helical polypeptide inhibitor targeting HRas protein and its application should be solved The polypeptide inhibitors in the prior art have the technical problems of weak cell membrane penetrating ability and low binding affinity with HRas

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  • A kind of α-helical polypeptide inhibitor targeting hras protein and its use
  • A kind of α-helical polypeptide inhibitor targeting hras protein and its use
  • A kind of α-helical polypeptide inhibitor targeting hras protein and its use

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Embodiment 1

[0042] Preparation and separation and purification steps of the polypeptide of embodiment 1:

[0043] Using solid-phase synthesis to synthesize peptides, the core steps for preparing the above-mentioned stable peptides are as follows (taking H5 peptide as an example):

[0044]

[0045] The specific operation steps are:

[0046] (1) Polypeptide solid-phase synthesis: Weigh Rink amide MBHA resin in the peptide tube and use morpholine / N,N-dimethylformamide with a reagent volume ratio of 50% (v / v) in the peptide tube (DMF) removes the Fmoc protecting group on the resin, in N 2 React under blowing, 30min / time, a total of two times, so that the resin exposes free amino groups. Then use DMF solvent / dichloromethane (DCM) / N-methylpyrrolidone (NMP) and other solvents to wash alternately 6-9 times respectively. Then add 5eq Fmoc-protected amino acid but carboxyl exposed amino acid, 5eq HCTU, 10eq DIPEA, in N 2 React under agitation, 1h / time, react 2 times. Then alternately wash 6...

Embodiment 2

[0048] Example 2 Fluorescence Polarization (FP) Experimental Screening of Polypeptides Combined with HRas

[0049] In the present invention, fluorescence polarization (FP) experiment is used to measure the binding affinity between FITC-labeled polypeptide and HRas protein, and the experimental results are summarized in Table 1. According to the results of the FP experiment, the linear polypeptide L1 only shows a weak interaction with the HRas protein, indicating that the affinity between the linear polypeptide L1 and HRas is weak, and as the original sequence based on the key fragment of the Sos protein, it can be used as a follow-up experiment the control peptide.

[0050] The peptides H3 and H4 designed based on the peptide sequence (FEGIYRLELLKAEEAN) have a certain interaction with HRas, but the binding affinity is above the micromolar level, and the binding affinity is weak, indicating that the inhibitor designed based on the peptide sequence needs further research. Only ...

Embodiment 3

[0053] The circular dichroism spectrum result of embodiment 3Ras polypeptide

[0054] In order to determine the secondary conformation of the polypeptide in aqueous solution, the present invention uses a circular dichroism spectrometer to measure the circular dichroism (CD) spectrum of the polypeptide. According to the characteristic negative absorption peaks near 208nm and 222nm and the characteristic positive absorption peak near 190nm in the circular dichroism spectrum, it can be judged that the polypeptide has a typical α-helical conformation. The results of CD experiments showed that peptides H2, H3, H5, H8, H10, and H11, which were ring-closed with terminal aspartic acid nucleating templates, displayed typical α-helical conformations in their circular dichroism (CD) assays ( figure 2 ), while the unclosed linear polypeptide L1 showed a random coil conformation, which confirmed that the TD-terminal nucleation template can stabilize the polypeptide in the α-helical confor...

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Abstract

The present invention is an α-helical polypeptide inhibitor targeting HRas protein, and its structural formula is as follows: The present invention also provides the use of the above-mentioned polypeptide inhibitor in the preparation of drugs for targeting HRas protein. The α-helical polypeptide inhibitor targeting HRas protein of the present invention can be applied to radiation sensitizers for radiotherapy.

Description

technical field [0001] The invention belongs to the field of bioengineering, and relates to a polypeptide, specifically an alpha-helical polypeptide inhibitor targeting HRas protein and its application. Background technique [0002] There are three main treatment modalities in the field of cancer treatment: radiation therapy, chemotherapy and surgery. Radiation therapy is one of the important non-surgical treatments for cancer. Radiation therapy is called an "invisible scalpel", which can preserve organs and their functions, and achieve the goal of minimally invasive and efficient treatment of tumors, such as the treatment of nasopharyngeal carcinoma. Due to the anatomical location of the nasopharynx and its special location, surgical treatment is very difficult , but nasopharyngeal cancer cells are more sensitive to radiation, so radiotherapy is an ideal treatment for nasopharyngeal carcinoma, and the strategy of radiotherapy for early nasopharyngeal carcinoma patients can ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08A61K38/10A61K38/07A61P35/00
CPCC07K7/08A61K38/07A61P35/00A61K38/00A61K2300/00
Inventor 李子刚尹丰覃伟容廉晨珊
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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