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

Ashleigh Shannon, Barbara Selisko, Nhung-Thi-Tuyet Le, Johanna Huchting, Franck Touret, Géraldine Piorkowski, Véronique Fattorini, François Ferron, Etienne Decroly, Chris Meier, Bruno Coutard, Olve Peersen () and Bruno Canard ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18463-z

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