A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle
A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle
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DOI：
10.1073/pnas.0915117107
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发表时间：
2010-02-23
影响因子：
11.1
通讯作者：
Chen, Zhilei
中科院分区：
文献类型：
--
作者：
Chockalingam, Karuppiah;Simeon, Rudo L.;Chen, Zhilei
丙型肝炎病毒（HCV）的生命周期涉及多个步骤，但目前大多数候选药物仅针对病毒复制。不能系统地发现针对HCV生命周期多个步骤的抑制剂阻碍了抗病毒药物的开发。我们提出了一个简单的筛选HCV抗病毒药物的基础上减轻HCV介导的细胞病变效应的工程细胞系-n4 mBid。这种方法消除了对二次筛选的需要，以避免细胞毒性假阳性命中。将我们的筛选应用于1280种化合物，其中许多处于临床试验中或被批准用于治疗用途，产生了>200个命中。在55个主要命中中，47个抑制HCV生命周期的一个或多个方面> 40%。六种化合物阻断HCV进入至与靶向HCV进入受体CD 81的抗体（JS-81）相似的水平。七次命中抑制HCV复制和/或感染性病毒产生> 100倍，其中一次（奎尼丁）相对于HCV复制水平抑制感染性病毒产生450倍。这种方法简单、便宜，应该能够快速发现新的HCV生命周期抑制剂。
The hepatitis C virus (HCV) life cycle involves multiple steps, but most current drug candidates target only viral replication. The inability to systematically discover inhibitors targeting multiple steps of the HCV life cycle has hampered antiviral development. We present a simple screen for HCV antivirals based on the alleviation of HCV-mediated cytopathic effect in an engineered cell line-n4mBid. This approach obviates the need for a secondary screen to avoid cytotoxic false-positive hits. Application of our screen to 1280 compounds, many in clinical trials or approved for therapeutic use, yielded >200 hits. Of the 55 leading hits, 47 inhibited one or more aspects of the HCV life cycle by >40%. Six compounds blocked HCV entry to levels similar to an antibody (JS-81) targeting the HCV entry receptor CD81. Seven hits inhibited HCV replication and/or infectious virus production by > 100-fold, with one (quinidine) inhibiting infectious virus production by 450-fold relative to HCV replication levels. This approach is simple and inexpensive and should enable the rapid discovery of new classes of HCV life cycle inhibitors.