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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection
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Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection

机译：整个丙型肝炎病毒生命周期的无偏探测可确定针对感染多个方面的临床化合物

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摘要

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.
机译：超过1亿7千万人长期受到丙型肝炎病毒（HCV）感染，并有死于肝硬化和肝细胞癌的危险。当前的疗法是昂贵的，伴有明显的副作用，并且通常是无效的。传统上，针对HCV的抗病毒化合物的发现涉及先验的目标识别，然后在基于细胞的复制子测定中进行生化筛选和确认。典型地，这导致发现了针对一些预定靶标并且易于选择逃逸变体的化合物。为了尝试鉴定具有广泛靶标特异性的抗病毒化合物，我们开发了一种无偏见的基于细胞的筛选系统，该系统涉及96孔格式的多轮感染。对446种临床批准药物的公共库进行分析，确定了33种针对HCV感染的已知和先前未开发方面的化合物，包括进入，复制和组装。以这种方式发现新的病毒和细胞靶标将扩大针对该病毒的治疗装备，从而允许开发药物混合物，该混合物应减少突变逃逸的可能性。

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