1. Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus
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Arielle R. Rosenberg, Yves Rouillé, Laurence Cocquerel, Czeslaw Wychowski, Thibaut Vausselin, Adeline Danneels, Ahmed Atef Ahmed Abouzeid Mesalam, Matthieu Lemasson, Sandrine Belouzard, Karin Séron, Muriel Lavie, Jean Dubuisson, Patricia Melnyk, Lucie Fénéant, Lander Foquet, Philip Meuleman, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), the ANR through ERA-NET Infect-ERA program (ANR-13-IFEC-0002-01). Philip Meuleman was supported by Ghent University (Concerted Action Grant 01G01712) and the Belgian Science Policy Office (BELSPO, IUAP P7/47-HEPRO-2). Thibaut Vausselin and Matthieu Lemasson were supported by a fellowship from the ANRS. Sandrine Belouzard was supported by a Marie Curie International Reintegration Grant (PIRG-GA-2009-256300). Ahmed Atef Mesalam is the recipient of a Ph.D. fellowship provided by the Egyptian Government. The 300-MHz NMR facilities were funded by the Région Nord-Pas de Calais (France), the Ministère de la Jeunesse, de l'Education Nationale et de la Recherche (MJENR), and the Fonds Européens de Développement Régional (FEDER)., We thank P.-E. Larchanché for the synthesis of the compounds. We are grateful to Gilles Duverlie and Véronique Descamps for core protein quantification. We thank Laure Saas for technical assistance. We are also grateful to R. Bartenschlager, C. Biot, J. Bukh, F.L. Cosset, P. Halfon, J. McKeating, and T. Wakita for providing essential reagents. The immunofluorescence analyses were performed with the help of the imaging core facility of the BioImaging Center Lille Nord-de-France., ANR-13-IFEC-0002,HCV-ASSEMBLY,Identification of host factors involved in Hepatitis C Virus assembly and characterization of their potential role in vivo(2013), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Universiteit Gent = Ghent University [Belgium] (UGENT), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University (UGENT), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
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Models, Molecular ,0301 basic medicine ,Hepacivirus ,Hepatitis C virus ,Immunology ,Drug Evaluation, Preclinical ,Mutation, Missense ,Mice, SCID ,Drug resistance ,Pharmacology ,medicine.disease_cause ,Antiviral Agents ,Microbiology ,Virus ,Mice ,03 medical and health sciences ,Viral Envelope Proteins ,[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication ,Viral entry ,Virology ,Vaccines and Antiviral Agents ,Drug Resistance, Viral ,medicine ,Animals ,Humans ,Cells, Cultured ,Mutation ,Molecular Structure ,biology ,Hepatitis C ,Virus Internalization ,biology.organism_classification ,Resistance mutation ,medicine.disease ,Reverse Genetics ,3. Good health ,Disease Models, Animal ,Treatment Outcome ,030104 developmental biology ,Insect Science ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Aminoquinolines ,Hepatocytes - 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. IMPORTANCE 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.
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- 2016