Chemical genetics approach to hepatitis C virus replication: cyclophilin as a target for anti‐hepatitis C virus strategy
Chemical genetics approach to hepatitis C virus replication: cyclophilin as a target for anti‐hepatitis C virus strategy
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DOI：
10.1002/rmv.534
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发表时间：
2007-07
影响因子：
11.1
通讯作者：
Koichi Watashi;K. Shimotohno
中科院分区：
文献类型：
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作者：
Koichi Watashi;K. Shimotohno
丙型肝炎病毒（HCV）是慢性肝炎、肝硬化和肝细胞癌等肝脏疾病的主要病原体。由于目前的标准疗法，干扰素（IFN）或聚乙二醇干扰素单独或与利巴韦林联合，对大约一半的HCV感染患者无效，因此非常需要替代疗法。化学遗传学方法是阐明病毒生命周期的分子机制和筛选抗病毒药物的有用策略。本文综述了化学遗传学方法在病毒学研究中的应用，并介绍了一个应用实例。从基于细胞培养的筛选中，免疫抑制剂环孢菌素A（CsA）被鉴定为抗HCV化合物。以CsA作为生物探针的分析表明，亲环素（CyP）B是CsA的细胞靶点，可调节HCV RNA聚合酶NS5 B的功能，而NS5 B是病毒基因组有效复制所必需的。通过靶向CyP，HCV基因组复制被显著抑制。因此，化学遗传学分析确定CyPB是HCV基因组复制的细胞辅因子和新型抗HCV药物的靶点。版权所有© 2007约翰威利父子有限公司。
Hepatitis C virus (HCV) is a major causative agent of liver diseases such as chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Because the current standard therapy, interferon (IFN) or pegylated‐IFN alone or in combination with ribavirin, is ineffective on approximately half of the HCV‐infected patients, alternative therapeutics are greatly needed. The chemical genetics method is a useful strategy to elucidate molecular mechanisms of the viral life cycle and screen for anti‐viral agents. This review focuses on the use of chemical genetics approach to virology, which could be called ‘chemical virology’, and introduces an example of such analysis. From a cell culture‐based screening, an immunosuppressant cyclosporin A (CsA) was identified as an anti‐HCV compound. Analysis using CsA as a bioprobe showed that cyclophilin (CyP) B, a cellular target of CsA, regulates the function of HCV RNA polymerase NS5B, which is essential for efficient viral genome replication. By targeting CyP, HCV genome replication was drastically suppressed. Thus, chemical genetics analysis identified CyPB as a cellular cofactor of HCV genome replication and a target for novel anti‐HCV agents. Copyright © 2007 John Wiley & Sons, Ltd.