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

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.
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https://www.hal.inserm.fr/inserm-03052188
Contributor : François Ferron Connect in order to contact the contributor
Submitted on : Friday, December 11, 2020 - 1:45:55 PM
Last modification on : Wednesday, January 19, 2022 - 4:58:38 PM
Long-term archiving on: : Friday, March 12, 2021 - 7:38:08 PM

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Ashleigh Shannon, Barbara Selisko, Nhung-Thi-Tuyet Le, Johanna Huchting, Franck Touret, et al.. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis. Nature Communications, Nature Publishing Group, 2020, 11 (1), pp.4682. ⟨10.1038/s41467-020-18463-z⟩. ⟨inserm-03052188⟩

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