Identification of a new benzimidazole derivative as an antiviral against hepatitis C virus

Thibaut Vausselin, Karin Séron, Muriel Lavie, Ahmed Atef Mesalam, Matthieu Lemasson, Sandrine Belouzard, Lucie Fénéant, Adeline Danneels, Yves Rouillé, Laurence Cocquerel, Lander Foquet, Arielle R. Rosenberg, Czeslaw Wychowski, Philip Meuleman, Patricia Melnyk, Jean Dubuisson

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Aminoquinolines and piperazines, linked or not, have been used successfully to treat malaria, and some molecules of this family also exhibit antiviral properties. Here we tested several derivatives of 4-aminoquinolines and piperazines for their activity against hepatitis C virus (HCV). We screened 11 molecules from three different families of compounds, and we identified anti- HCV activity in cell culture for six of them. Of these, we selected a compound (B5) that is currently ending clinical phase I evaluation for neurodegenerative diseases. In hepatoma cells, B5 inhibited HCV infection in a pangenotypic and dose-dependent manner, and its antiviral activity was confirmed in primary hepatocytes. B5 also inhibited infection by pseudoparticles expressing HCV envelope glycoproteins E1 and E2, and we demonstrated that it affects a postattachment stage of the entry step. Virus with resistance to B5 was selected by sequential passage in the presence of the drug, and reverse genetics experiments indicated that resistance was conferred mainly by a single mutation in the putative fusion peptide of E1 envelope glycoprotein (F291I). Furthermore, analyses of the effects of other closely related compounds on the B5-resistant mutant suggest that B5 shares a mode of action with other 4-aminoquinoline-based molecules. Finally, mice with humanized liver that were treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle.

Original languageEnglish
Pages (from-to)8422-8434
Number of pages13
JournalJournal of Virology
Volume90
Issue number19
DOIs
StatePublished - 2016

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