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.
Keywords: Anti-viral; HCV; Heterocycle; Indole; RdRp; Thumb site I.
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