title: Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus.
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.
  
  
  
  In the last 4 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. The present study reports the identification and characterization of a compound (B5) 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 B5 could be used to further investigate the fusion mechanism. Furthermore, mice with humanized liver 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.
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Vausselin
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Séron
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Lavie
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Ahmed Atef
authors.initials: AA
authors.lastname: Mesalam
authors.affiliation: Université Paris Descartes, Hepatitis C Virology, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lemasson
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Belouzard
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Fénéant
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Danneels
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Rouillé
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cocquerel
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Lander
authors.initials: L
authors.lastname: Foquet
authors.affiliation: Université Paris Descartes, Hepatitis C Virology, Paris, France.
authors.forename: Arielle R
authors.initials: AR
authors.lastname: Rosenberg
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Czeslaw
authors.initials: C
authors.lastname: Wychowski
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.affiliation: Université Lille, Inserm, CHU Lille, UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, Lille, France patricia.melnyk@univ-lille2.fr jean.dubuisson@ibl.cnrs.fr.
authors.forename: Patricia
authors.initials: P
authors.lastname: Melnyk
authors.affiliation: Université Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-Centre d'Infection et d'Immunité de Lille, Lille, France patricia.melnyk@univ-lille2.fr jean.dubuisson@ibl.cnrs.fr.
authors.forename: Jean
authors.identifier: 0000-0003-1626-7693
authors.initials: J
authors.lastname: Dubuisson
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D020125:Mutation, Missense; D059386:Reverse Genetics; D016896:Treatment Outcome; D014759:Viral Envelope Proteins / Q000235:genetics; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D000998:Antiviral Agents; C087035:E1 protein, Hepatitis C virus; D014759:Viral Envelope Proteins; C001920:4-aminoquinoline