The antimalarial ferroquine is an inhibitor of hepatitis C virus

Autor: Thibaut Vausselin, Lucie Fénéant, Catherine François, Yann Guérardel, Sandrine Belouzard, Véronique Descamps, Jean Dubuisson, François Helle, Czeslaw Wychowski, Gilles Duverlie, Ahmed Wahid, Dimitri Lavillette, Noémie Calland, Florian Douam, Christophe Biot, Laurence Cocquerel
Přispěvatelé: Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, LillOA, 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), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Proline
Metallocenes
Viral Hepatitis
Hepatitis C virus
media_common.quotation_subject
Hepacivirus
Viral Nonstructural Proteins
Biology
Virus Replication
medicine.disease_cause
Antiviral Agents
Virus
03 medical and health sciences
0302 clinical medicine
Viral Envelope Proteins
Viral life cycle
Interferon
Chloroquine
Cell Line
Tumor
medicine
Humans
Ferrous Compounds
Internalization
Neutralizing antibody
030304 developmental biology
media_common
0303 health sciences
Hepatology
Interferon-alpha
virus diseases
Drug Synergism
Virus Internalization
Hepatitis C
Virology
[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
digestive system diseases
3. Good health
[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry
[CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry
Cell culture
Aminoquinolines
biology.protein
030211 gastroenterology & hepatology
[SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
medicine.drug
Zdroj: Hepatology
Hepatology, 2013, Hepatology, 58 (1), pp.86-97. ⟨10.1002/hep.26273⟩
Hepatology (Baltimore, Md.)
ISSN: 0270-9139
1527-3350
Popis: Hepatitis C virus (HCV) is a major cause of chronic liver disease. Despite recent success in improving anti‐HCV therapy, additional progress is still needed to develop cheaper and interferon (IFN)‐free treatments. Here, we report that ferroquine (FQ), an antimalarial ferrocenic analog of chloroquine, is a novel inhibitor of HCV. FQ potently inhibited HCV infection of hepatoma cell lines by affecting an early step of the viral life cycle. The antiviral activity of FQ on HCV entry was confirmed with pseudoparticles expressing HCV envelope glycoproteins E1 and E2 from six different genotypes. In addition to its effect on HCV entry, FQ also inhibited HCV RNA replication, albeit at a higher concentration. We also showed that FQ has no effect on viral assembly and virion secretion. Using a binding assay at 4°C, we showed that FQ does not prevent attachment of the virus to the cell surface. Furthermore, virus internalization was not affected by FQ, whereas the fusion process was impaired in the presence of FQ as shown in a cell‐cell fusion assay. Finally, virus with resistance to FQ was selected by sequential passage in the presence of the drug, and resistance was shown to be conferred by a single mutation in E1 glycoprotein (S327A). By inhibiting cell‐free virus transmission using a neutralizing antibody, we also showed that FQ inhibits HCV cell‐to‐cell spread between neighboring cells. Combinations of FQ with IFN, or an inhibitor of HCV NS3/4A protease, also resulted in additive to synergistic activity. Conclusion: FQ is a novel, interesting anti‐HCV molecule that could be used in combination with other direct‐acting antivirals. (Hepatology 2013)
Databáze: OpenAIRE
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