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Application of cdk2 kinase inhibitor in preparation of hepatitis B therapeutic drug

A kinase inhibitor, hepatitis B technology, applied in the field of drug research and development, can solve the problem of unclear regulation of host protein kinase phosphorylation, and achieve the effect of broad application prospects

Active Publication Date: 2021-01-15
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, how SAMHD1 is regulated by phosphorylation by host protein kinases during HBV infection remains unclear

Method used

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  • Application of cdk2 kinase inhibitor in preparation of hepatitis B therapeutic drug
  • Application of cdk2 kinase inhibitor in preparation of hepatitis B therapeutic drug
  • Application of cdk2 kinase inhibitor in preparation of hepatitis B therapeutic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 Identification and screening of host protein kinases involved in regulating the phosphorylation of restriction factor SAMHD1 In order to identify and screen host protein kinases involved in the regulation of phosphorylation of restriction factor SAMHD1, the applicant specifically interfered with cyclin-dependent kinase (cyclin -dependent kinases, CDK1, CDK2 and CDK6) (interfering sequence as shown in Table 2 in embodiment 2) expression, analyze the change of virus replication level and the change of SAMHD1 phosphorylation level (analysis method and the analysis in embodiment 2 The method is the same): the results show that (such as figure 1 (shown) After interfering with the expression of CDK2 kinase, it can obviously lead to a decrease in the phosphorylation of the restriction factor SAMHD1 and a decrease in the level of HBV replication, indicating that CDK2 kinase is involved in the phosphorylation of the restriction factor SAMHD1, and CDK2 / SAMHD1 can be used...

Embodiment 2

[0019] On the basis of the applicant's research in Example 1: it was found that CDK2 kinase inhibitors can inhibit HBV replication by inhibiting the phosphorylation of the host-restricted factor SAMHD1; in the HBV replication transfection model and based on NTCP-HepG2.0 In the infection model, small molecular compounds that exert antiviral effects were screened from existing CDK2 kinase inhibitors. The experimental procedure is:

[0020] (1): Firstly, the toxicity of CDK2 kinase inhibitors from Selleck Company, Santa Company and Merckmillipore Company to hepatocytes was detected by MTT method in the cell line HepAD38 cells with stable replication of HBV;

[0021] (2) In the cell line HepAD38 cells of HBV stably replicated in co-transfected SAMHD1, detect the effect of the above-mentioned CDK2 kinase inhibitor on the inhibition of virus replication and the phosphorylation of host restriction factor SAMHD1;

[0022] (3) On the HBV infection model based on NTCP-HepG2.0, verify t...

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PUM

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Abstract

The invention discloses application of a CDK2 (Cyclin-Dependent Kinase2) kinase inhibitor in preparation of a medicine for treating hepatitis B. In numerous CDK kinase inhibitors, the CDK2 kinase inhibitor is capable of obviously inhibiting HBV (Hepatitis B Virus) replication, and the inhibitory effect is discovered to depend on a host limiting factor SAMHD1; and experiments prove that the CDK2 inhibitor II is capable of inhibiting the HBV replication. Moreover, the compound has very light toxicity on hepatic cells, the half toxicity constant TC 50 is more than 50uM, and virus replication canbe obviously inhibited on an HBV replication transfection model, an HBV stable replication HepAD38 and an NTCP-HepG2.0 based HBV infection model. Therefore, the CDK2 inhibitor II can be used in preparation of a medicine for treating chronic hepatitis B infection and has wide application prospects.

Description

technical field [0001] The invention relates to the field of drug research and development, in particular to the application of a CDK2 kinase inhibitor in the preparation of drugs for treating hepatitis B. Background technique [0002] Hepatitis B virus (HBV) is a hepatotropic DNA virus, and its infection is widespread worldwide. There are about 2.5 million chronic hepatitis B patients in the world. HBV infection is divided into acute and chronic infections, among which chronic infection can cause chronic hepatitis B (CHB), liver cirrhosis (LC) and primary hepatocellular carcinoma (HCC) and other related diseases, and HCC caused by chronic HBV infection is the second largest in the world 5 digits. At present, there are still more than 80 million HBV chronically infected patients in China, and the primary goal of treating chronic hepatitis B is to suppress virus replication for a long time. [0003] Currently, there are two main antiviral drugs for the treatment of chronic ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/635A61P31/20
CPCA61K31/635A61P31/20
Inventor 胡源黄爱龙胡杰乔淼陈彦猛
Owner CHONGQING MEDICAL UNIVERSITY