Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors
Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors
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DOI：
10.1021/jm401793m
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发表时间：
2014-03-13
影响因子：
7.3
通讯作者：
Meanwell, Nicholas A.
中科院分区：
文献类型：
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作者：
Belema, Makonen;Lopez, Omar D.;Meanwell, Nicholas A.
针对丙型肝炎病毒(丙型肝炎病毒)非结构5A(NS5A)蛋白功能的先导抑制剂已经通过使用丙型肝炎病毒亚基因组复制子的表型筛选活动确定。丙型肝炎病毒NS5A复制复合体抑制剂(RCI)达拉塔韦(1)在丙型肝炎病毒感染者中的抗病毒活性的证明引起了人们对这种机制方法的浓厚兴趣。在这一视角下，我们总结了导致1和其他耐药映射到NS5A蛋白的化学类型的药物化学研究，并提供了目前正在进行临床试验的许多化合物的概要。我们还总结了目前关于NS5A蛋白的已知情况，以及使用NS5A RCIS和标记类似物的研究，这些研究有助于阐明蛋白质功能和抑制剂相互作用的各个方面。最后，我们简要介绍了丙型肝炎病毒NS5A RCIS的显著临床试验结果。
Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.