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Polypeptide inhibitor and application thereof

A polypeptide inhibitor and sequence technology, applied in the fields of chemical biology and computational chemistry, can solve the problems of poor efficacy of Alzheimer's disease, achieve the effect of reducing the production of oligomers and reducing toxicity

Inactive Publication Date: 2021-02-02
PEKING UNIV SHENZHEN GRADUATE SCHOOL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The present invention takes the emerging secondary nucleation theory as the starting point, and according to the structural characteristics of the Aβ fiber surface, combined with computational simulation and experimental means, designs a polypeptide inhibitor that can inhibit the production of highly toxic oligomers to solve the problem of the prior art The problem with drugs that don't work well in Alzheimer's

Method used

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  • Polypeptide inhibitor and application thereof
  • Polypeptide inhibitor and application thereof
  • Polypeptide inhibitor and application thereof

Examples

Experimental program
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Embodiment 1

[0040] The design of embodiment 1 polypeptide inhibitor

[0041] The present invention analyzes the binding mode of Aβ40 monomer and Aβ40 fiber by means of computational simulation, and the model diagram of the mixed system of Aβ40 monomer and Aβ40 fiber is as follows figure 2 shown. Specifically, first select one of the fiber chains from the solved Aβ40 fiber structure (PDB ID: 2LMN) as a template and place it on the xy-plane, along the direction of the z-axis to The fiber chain is translated at intervals of , and finally a fiber containing 12 chains is obtained, the fiber axis coincides with the z-axis, and the simulated box is a cuboid box ( figure 2 a). In order to obtain a one-dimensional infinitely long fiber model, the periodic boundary condition of the simulation box is used here, so that the distance between the two chains of the adjacent box is also equal to The advantage of the one-dimensional infinitely long fiber model is that it restores the ratio of fiber...

Embodiment 2

[0054] Example 2 Binding mode of cHASI--1 and Aβ40 fibers

[0055] Since Aβ40 is highly heterogeneous, we cannot rule out that cHASI-1 can also interact with Aβ40 monomers as well as oligomers. In order to better demonstrate the type of binding of cHASI-1 to Aβ40, we detected the binding ability of cHASI-1 to freshly prepared Aβ40 monomers. Size exclusion chromatography (size exclusion chromatograms) showed that only Aβ40 monomer ( Figure 8 ). Both FP and ITC experiments failed to detect the obvious interaction between cHASI-1 and Aβ40 monomer ( Figure 4 B and Figure 5 G). Therefore, cHASI-1 is unlikely to interact with Aβ40 monomers. According to the preparation method of Luo et al., we prepared Aβ40 oligomers, and measured the binding ability of cHASI-1 and Aβ40 oligomers (16.5 μM) by FP method ( Figure 4 B). Thus, cHASI-1 exhibited moderate binding ability to Aβ40 oligomers and strong binding ability to Aβ40 fibrils. We conclude that cHASI-1 can specifically rec...

Embodiment 3

[0059] Example 3 cHASI-1 can specifically inhibit the pathway of Aβ40 fiber secondary nucleation to generate oligomers

[0060] We used Thioflavin T (ThT) to measure Aβ40 aggregation, and explored how different concentrations of cHASI-1 affect the kinetics of Aβ40 aggregation. We first obtained the Aβ40 monomer by FPLC separation. This is to ensure that the initial state of Aβ40 (including only primary nucleation) does not contain existing fibers. The fibers existing in this system are called "seeds" (seeds). ), they will greatly promote the aggregation of Aβ40 (secondary nucleation, and elongation) ( Figure 8 ). In all cases, the aggregation kinetics curves exhibited a typical S-shaped curve, including a lag phase, a growth phase, and a plateau ( figure 1 ), see the Front and Background section for more details. cHASI-1 can effectively slow down the lag phase of 10μM Aβ40 monomer aggregation in a concentration-dependent manner (1-5 equivalents, 10-50μM) ( Figure 13 A) W...

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Abstract

The invention discloses a polypeptide inhibitor. The sequence of the polypeptide inhibitor is Cyclo (isoD3-F4R5-Dap6)-D7-V8-R9-A10-E11-R12-A13-E14. The invention further provides application of the polypeptide inhibitor in preparation of medicine for treating Alzheimer's disease. According to the polypeptide inhibitor, molecules in a spiral mode can be used as a skeleton to identify a fiber surface. Experiments prove that the polypeptide inhibitor can be used for specifically inhibiting the combination of an Abeta40 monomer and the fiber surface and blocking a way of forming a toxic oligomer by Abeta40 secondary nucleation, so that the toxicity of Abeta40 to human cells is reduced; free amino groups at the N end of polypeptide can be further chemically modified and further applied to imaging of the Abeta40 and the like; and the polypeptide can be used as potential medicine for treating and diagnosing Alzheimer's disease.

Description

technical field [0001] The invention belongs to the fields of chemical biology and computational chemistry, and relates to a polypeptide, in particular to the design, preparation and use of a polypeptide inhibitor. Background technique [0002] Alzheimer's disease (Alzheimer's Disease, AD) is a serious disease with progressive cognitive decline and loss of independence. Its main manifestations are brain atrophy, degeneration of memory and cognitive learning ability, and the slow deterioration over time will bring a heavy burden to the society and the family. Therefore, there is an urgent need in society to develop drugs and therapies for this disease. [0003] There are many hypotheses about the pathogenesis of Alzheimer's disease, among which the amyloid (Aβ) hypothesis is the most studied. Studies have found that non-plaque Aβ oligomer protein (aggregation of many Aβ monomers) is the main pathogenic form of Aβ. These toxic oligomeric proteins, also known as amyloid-deri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47A61K38/17A61P25/28
CPCC07K14/4711A61P25/28A61K38/00
Inventor 李子刚尹丰杨发灯
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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