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

Nature Communications
Bruno CanardBruno Canard

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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Datasets Mentioned

BETA
PRJNA633443
MT594401
MT594402

Methods Mentioned

BETA
size
gel filtration
electrophoresis
fluorescence imager
FCS
Assay
PCR

Software Mentioned

Systat
Image Gauge
ImageQuant
CLC genomics workbench
ImageJ
PeakFit
KinTek Explorer
GraphPad Prism
Graph pad
AB Library Builder System

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