1. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis.
- Author
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Shannon A, Selisko B, Le NT, Huchting J, Touret F, Piorkowski G, Fattorini V, Ferron F, Decroly E, Meier C, Coutard B, Peersen O, and Canard B
- Subjects
- Amides pharmacokinetics, Animals, Antiviral Agents pharmacokinetics, COVID-19, Chlorocebus aethiops, Coronavirus Infections virology, Coronavirus RNA-Dependent RNA Polymerase, Models, Molecular, Mutagenesis drug effects, Pandemics, Pneumonia, Viral virology, Pyrazines pharmacokinetics, RNA, Viral genetics, RNA, Viral metabolism, RNA-Dependent RNA Polymerase chemistry, RNA-Dependent RNA Polymerase metabolism, SARS-CoV-2, Sequence Analysis, Vero Cells, Viral Nonstructural Proteins chemistry, Viral Nonstructural Proteins metabolism, Virus Replication drug effects, COVID-19 Drug Treatment, Amides pharmacology, Antiviral Agents pharmacology, Betacoronavirus drug effects, Betacoronavirus genetics, Coronavirus Infections drug therapy, Pneumonia, Viral drug therapy, Pyrazines pharmacology
- 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.
- Published
- 2020
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