Chemical genetics-based discovery of indole derivatives as HCV NS5B polymerase inhibitors

Guanghai Jin, Sungjin Lee, Moonju Choi, Seohyun Son, Geon Woo Kim, Jong Won Oh, Choongho Lee, Kyeong Lee

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36 Citations (Scopus)


In order to identify the inhibitors of hepatitis C virus (HCV) replication with a novel scaffold via a mechanistically unbiased approach, we screened our in-house library composed of ∼6000 compounds with various chemical structures by using the renilla luciferase-linked genotype 2a reporter virus, and we identified a series of compounds containing an indole moiety that were active against HCV replication. Based on this result, we further synthesized three groups of indole derivatives and evaluated their inhibitory effects on HCV replication. In the present structure-activity relationship study of these indole derivatives, we discovered that compound 12e was the most potent inhibitor of HCV replication with minimal cytotoxicity (EC50 = 1.1 μM, EC90 = 2.1 μM, and CC50 = 61.8 μM). We also confirmed that compound 12e caused a dose- and time-dependent reduction of viral RNA as well as viral protein levels in both genotype 2a J6/JFH1 RNA-transfected cells and genotype 1b Bart79I subgenomic replicon cells. Finally, a genetic mapping study of mutant viruses resistant to compound 12e revealed that NS5B RNA polymerase was the potential target. This finding was further validated by demonstration of inhibition of NS5B RNA polymerase in vitro by compound 12e (IC50 = 292 nM). Compound 12e may serve as a valuable candidate for the development of a new class of HCV NS5B RNA polymerase inhibitors in the future.

Original languageEnglish
Pages (from-to)413-425
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 2014 Mar 21

Bibliographical note

Funding Information:
This work was supported by the GRRC program of Gyeonggi province . [(GRRC-DONGGUK2011-A01), Study of control of viral diseases] [(GRRC-DONGGUK2011-B02), Development and discovery of new therapeutic target modulators] and a NRF grant ( 2012M3A9C1053532 ) from South Korea . This research was also supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2013R1A1A1011851 ).

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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