Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection
Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection
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DOI：
10.1073/pnas.0912966107
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
Chisari, Francis V.
中科院分区：
文献类型：
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作者：
Gastaminza, Pablo;Whitten-Bauer, Christina;Chisari, Francis V.
超过1.7亿人慢性感染丙型肝炎病毒（HCV），并有死于肝硬化和肝细胞癌的风险。目前的治疗是昂贵的，与显着的副作用，往往无效。抗HCV的抗病毒化合物的发现传统上涉及先验靶标鉴定，随后是基于细胞的复制子测定中的生物化学筛选和确认。通常，这导致发现了针对一些预定目标的化合物，并且倾向于选择逃逸变体。为了尝试鉴定具有广泛靶特异性的抗病毒化合物，我们开发了一种无偏倚的基于细胞的筛选系统，该系统涉及96孔格式中的多轮感染。对446种临床批准药物的公开库进行分析，确定了33种化合物，这些化合物针对HCV感染的已知和以前未探索的方面，包括进入，复制和组装。以这种方式发现新的病毒和细胞靶点将拓宽针对这种病毒的治疗手段，允许开发药物混合物，从而降低突变逃逸的可能性。
Over 170 million people are chronically infected by the hepatitis C virus (HCV) and at risk for dying from liver cirrhosis and hepatocellular carcinoma. Current therapy is expensive, associated with significant side effects, and often ineffective. Discovery of antiviral compounds against HCV traditionally involves a priori target identification followed by biochemical screening and confirmation in cell-based replicon assays. Typically, this results in the discovery of compounds that address a few predetermined targets and are prone to select for escape variants. To attempt to identify antiviral compounds with broad target specificity, we developed an unbiased cell-based screening system involving multiple rounds of infection in a 96-well format. Analysis of a publicly available library of 446 clinically approved drugs identified 33 compounds that targeted both known and previously unexplored aspects of HCV infection, including entry, replication, and assembly. Discovery of novel viral and cellular targets in this manner will broaden the therapeutic armamentarium against this virus, allowing for the development of drug mixtures that should reduce the likelihood of mutational escape.