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Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

Author

Listed:
  • Ashleigh Shannon

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

  • Barbara Selisko

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

  • Nhung-Thi-Tuyet Le

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

  • Johanna Huchting

    (Faculty of Sciences, Department of Chemistry, Organic Chemistry, University of Hamburg)

  • Franck Touret

    (Unité des Virus Émergents (UVE: Aix-Marseille Univ - IRD 190 - Inserm 1207 - IHU Méditerranée Infection))

  • Géraldine Piorkowski

    (Unité des Virus Émergents (UVE: Aix-Marseille Univ - IRD 190 - Inserm 1207 - IHU Méditerranée Infection))

  • Véronique Fattorini

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

  • François Ferron

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

  • Etienne Decroly

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

  • Chris Meier

    (Faculty of Sciences, Department of Chemistry, Organic Chemistry, University of Hamburg)

  • Bruno Coutard

    (Unité des Virus Émergents (UVE: Aix-Marseille Univ - IRD 190 - Inserm 1207 - IHU Méditerranée Infection))

  • Olve Peersen

    (Colorado State University)

  • Bruno Canard

    (Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille Université)

Abstract

The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19.

Suggested Citation

  • Ashleigh Shannon & Barbara Selisko & Nhung-Thi-Tuyet Le & Johanna Huchting & Franck Touret & Géraldine Piorkowski & Véronique Fattorini & François Ferron & Etienne Decroly & Chris Meier & Bruno Coutar, 2020. "Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18463-z
    DOI: 10.1038/s41467-020-18463-z
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    Cited by:

    1. Romain Marlin & Delphine Desjardins & Vanessa Contreras & Guillaume Lingas & Caroline Solas & Pierre Roques & Thibaut Naninck & Quentin Pascal & Sylvie Behillil & Pauline Maisonnasse & Julien Lemaitre, 2022. "Antiviral efficacy of favipiravir against Zika and SARS-CoV-2 viruses in non-human primates," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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