Abstract
Hepatitis C virus (HCV) NS5B RNA-depended-RNA-polymerase (RdRp) is an essential enzyme in HCV viral replication and has no functional equivalent in mammalian cells. Several classes of nucleoside and non-nucleoside inhibitors, targeting the different allosteric sites, have demonstrated efficacy in clinical trials. Compared to other allosteric sites, thumb site I is a more compelling allosteric target with a significant number of inhibitors in clinical trials. Among them, indole analogues are the most important series of NS5B thumb site I inhibitors with considerable antiviral activity. This review focuses on the discovery and development of indole inhibitors targeting on NS5B thumb site I. Five fundamental principles, the general structure–activity relationships (SARs) model of indole scaffold, were summarized, which could pave the way for further structural optimization of indole-based anti-HCV agents.
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