Novel HCV Antiviral Screening in FRG Mice
Identification of a New Benzimidazole Derivative as an Antiviral Against Hepatitis C Virus
Vausselin et. al., 2016
In recent years, HCV therapy has been profoundly improved with the approval of direct-acting antivirals in clinical practice. Nevertheless, the high costs of these drugs limit access to therapy in most countries. This study reports the identification and characterization of a compound that inhibits HCV propagation in cell culture and is currently ending clinical phase I evaluation for neurodegenerative diseases. This molecule inhibits the HCV life cycle by blocking virus entry. Interestingly, after selection of drug-resistant virus, a resistance mutation in the putative fusion peptide of E1 envelope glycoprotein was identified, indicating that the drug could be used to further investigate the fusion mechanism. Furthermore, liver humanized FRG mice treated with the molecule showed a delay in the kinetics of the viral infection. In conclusion, the compound is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle.
Thibaut Vausselin, Karin Séron, Muriel Lavie, Ahmed Atef Mesalam, Matthieu Lemasson, Sandrine Belouzard, Lucie Fénéant, Adeline Danneels, Yves Rouillé, Laurence Cocquerel, Lander Foquetb, Arielle R. Rosenberg, Czeslaw Wychowski, Philip Meuleman, Patricia Melnyk, Jean Dubuisson
J Virol. 2016 Sep 12;90(19):8422-34
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 eleven 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 post-attachment 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 mainly conferred by a single mutation in the putative fusion peptide of E1 envelope glycoprotein (F291I). Furthermore, analyses of the effect of other closely related compounds on B5 resistant mutant, suggest that B5 shares a mode of action with other 4-aminoquinolines 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.