The antimalarial ferroquine is an inhibitor of hepatitis C virus

Authors

  • Thibaut Vausselin,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
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  • Noémie Calland,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
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  • Sandrine Belouzard,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
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  • Véronique Descamps,

    1. Laboratoire de Virologie EA4294, Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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  • Florian Douam,

    1. INSERM, U758, Human Virology Laboratory, Lyon, France
    2. Ecole Normale Supérieure de Lyon, Lyon, France
    3. Université de Lyon, UCB-Lyon1, Lyon, France
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  • François Helle,

    1. Laboratoire de Virologie EA4294, Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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  • Catherine François,

    1. Laboratoire de Virologie EA4294, Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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  • Dimitri Lavillette,

    1. INSERM, U758, Human Virology Laboratory, Lyon, France
    2. Ecole Normale Supérieure de Lyon, Lyon, France
    3. Université de Lyon, UCB-Lyon1, Lyon, France
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  • Gilles Duverlie,

    1. Laboratoire de Virologie EA4294, Centre Hospitalier Universitaire d'Amiens, Université de Picardie Jules Verne, Amiens, France
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  • Ahmed Wahid,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
    2. Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia, Egypt
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  • Lucie Fénéant,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
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  • Laurence Cocquerel,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
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  • Yann Guérardel,

    1. Université Lille Nord de France, Université Lille1, CNRS UMR8576, Villeneuve d'Ascq, France
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  • Czeslaw Wychowski,

    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
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  • Christophe Biot,

    1. Université Lille Nord de France, Université Lille1, CNRS UMR8576, Villeneuve d'Ascq, France
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  • Jean Dubuisson

    Corresponding author
    1. Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR8204, Lille, France; INSERM U1019, Lille, France; and Université Lille Nord de France, Lille, France
    • Molecular and Cellular Virology of Hepatitis C, CIIL, INSERM U1019 and CNRS UMR8204, Institut Pasteur de Lille, Bâtiment IBL, 1 rue Calmette, BP447, 59021 Lille, France===

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the French “Agence Nationale de la Recherche sur le Sida et les hépatites virales” (ANRS). T.V. was supported by a fellowship from the French Ministry of Research (MESR). N.C. was successively supported by a fellowship from the MESR and the ANRS. A.W. was supported by a postdoctoral fellowship of the ANRS. S.B. was supported by a Marie Curie International Reintegration Grant (PIRG-GA-2009-256300). The authors are grateful to J.K. Ball, R. Bartenschlager, 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.

Abstract

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)

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