HCV NS3/4A蛋白酶抑制剂药物及其耐药信息数据库的建立和应用

Establishment and application of a database for hepatitis C virus NS3/4A protease inhibitors and their drug resistance data

目的建立针对HCV NS3/4A蛋白酶的直接抗病毒药物(DAA)及相关耐药突变的数据库,并利用该数据库进行耐药性分析。方法收集、整理已经公开发表的蛋白酶抑制剂类DAA及耐药相关的数据和信息,将病毒突变体的体外耐药数据及临床治疗鉴定的耐药相关突变信息录入数据库,按照药物种类、病毒基因型别、耐药突变位置及突变氨基酸种类等的不同对这些信息进行统计分析,并将部分结果以网站的形式进行在线查询。以HCV难治性基因3型为例,利用该数据库对其进行多数据耐药分析。结果建立了HCV NS3/4A蛋白酶抑制剂类DAA及耐药信息数据库,部分数据已可在线查询,链接为http://www.biosino.org/hcv/。该数据库包括四个部分内容:DAA药物信息;含耐药突变的不同基因型病毒株的体外耐药信息;耐药相关突变的预存流行率以及在治疗失败患者中的检出率;DAA与NS3/4A蛋白酶复合物的三维结构图,共计上万条信息。利用该数据库分析了不同基因型HCV的耐药性,发现蛋白酶抑制剂药物对基因3型HCV治疗效果最差。尽管第三代抑制剂对基因3型野生型HCV具有较好的抗病毒效果,但是病毒极易出现耐药突变。结论该数据库是目前我国首个HCV蛋白酶抑制剂DAA及耐药信息数据库,为HCV耐药性研究及临床治疗用药提供了重要的信息来源和指导。

Objective To establish a database for direct-acting antiviral agents（DAAs） targeting hepatitis C virus（HCV） NS3/4 A protease and related resistance-associated variants,and to investigate its application in drug resistance analysis. Methods The published data and information of anti-NS3/4 A DAAs and related drug resistance data were collected and mined. The in vitro data of viral drug-resistant mutations and resistance-associated variants identified in clinical treatment were entered into the database,and a statistical analysis was performed based on the type of drugs,HCV genotypes,positions of drug-resistant mutations,and type of substituted amino acids. Some of the results were available for online query on a website. Then the database was used to perform a multi-data analysis of the drug resistance of genotype 3 HCV,a well-known difficult-to-treat viral genotype. Results A database for anti-NS3/4 A DAAs and their drug resistance data was established and some data were available for online query on a website（http：//www. biosino. org/hcv/）. This database consisted of the following four parts,with over ten thousands of pieces of information： the information of DAAs; the in vitro drug-resistance data of viral strains with different genotypes containing drug-resistant mutations; the prevalence of pre-existing resistance-associated variants and their detection rates in patients with treatment failure; the three-dimensional structures of the DAA-NS3/4 A protease complex.This database was used to analyze drug resistance of all genotypes of HCV,and it was found that anti-NS3/4 A DAAs had the poorest therapeutic effect in patients with genotype 3 HCV. Although the third-generation anti-NS3/4 A DAAs had a good antiviral effect in patients with wild-type genotype 3 HCV,drug-resistant mutations might occur. Conclusion This database is the first one in China for anti-NS3/4 A DAAs and their drug-resistance data and provides an important resource of information and guidance for research on drug resistance and clinical treatment of HCV.