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

by Selisko, Barbara , Touret, Franck , Architecture et fonction des macromolécules biologiques (AFMB) ; Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) , Ferron, Francois , Shannon, Ashleigh , Fattorini, Véronique , Canard, Bruno , Unité des Virus Emergents (UVE) ; Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM) , Peersen, Olve , Le, Nhung-Thi-Tuyet , ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2 , European Commission GA 871029SCORE project H2020 SC1-PHE-Coronavirus-2020 101003627United States Department of Health & Human Services National Institutes of Health (NIH) - USA AI059130 , Piorkowski, Géraldine , Colorado State University [Fort Collins] (CSU) , Huchting, Johanna , Meier, Chris , Universität Hamburg = University of Hamburg (UHH) , Decroly, Etienne , Coutard, Bruno , This work was supported by the

in 45/91 / 631/326/596/4130 / 631/45/612/1256 / 82/80 / 82/83 / Biochemistry, Molecular Biology / Humanities and Social Sciences / Life Sciences / Microbiology and Parasitology / Molecular biology / multidisciplinary / Pharmaceutical sciences / Pharmacology / Science / Science (multidisciplinary) / Virology

2020

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

2020

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

2020

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Journal Article

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

Selisko, Barbara,

Touret, Franck,

Architecture et fonction des macromolécules biologiques (AFMB) ; Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE),

Ferron, Francois,

Shannon, Ashleigh,

Fattorini, Véronique,

Canard, Bruno,

Unité des Virus Emergents (UVE) ; Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM),

Peersen, Olve,

Le, Nhung-Thi-Tuyet,

ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2,

European Commission GA 871029SCORE project H2020 SC1-PHE-Coronavirus-2020 101003627United States Department of Health & Human Services National Institutes of Health (NIH) - USA AI059130,

Piorkowski, Géraldine,

Colorado State University [Fort Collins] (CSU),

Huchting, Johanna,

Meier, Chris,

Universität Hamburg = University of Hamburg (UHH),

Decroly, Etienne,

Coutard, Bruno,

This work was supported by the

2020

Overview

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.

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Publisher

Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio

Subject

45/91

/ 631/326/596/4130

/ 631/45/612/1256

/ 82/80

/ 82/83

/ Biochemistry, Molecular Biology

/ Humanities and Social Sciences