title: Discovery of HCV NS5B thumb site I inhibitors: core-refining from benzimidazole to indole scaffold.
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.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
authors.forename: Fabao
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Department of Hepatic Diseases, Jinan Infectious Disease Hospital, Jingshi Road, 173, 250021 Jinan, Shandong, PR China. Electronic address: shdjxm@163.com.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012 Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry*; D018360:Crystallography, X-Ray; D007211:Indoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D007211:Indoles; D017361:Viral Nonstructural Proteins; C031000:benzimidazole; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Anti-viral; HCV; Heterocycle; Indole; RdRp; Thumb site I