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

The ongoing COVID-19 pandemic caused by SARS-CoV-2 highlights the need for antivirals. The viral RNA-dependent RNA polymerase (RdRp) is a promising target, as polymerase inhibitors are effective against several viruses. This study demonstrates that favipiravir predominantly exerts antiviral activity against SARS-CoV-2 via lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than other known viral RdRps, exhibiting unusually high nucleotide incorporation and error rates that facilitate favipiravir insertion into viral RNA, provoking C-to-U and G-to-A transitions in the cytosine-low SARS-CoV-2 genome. These findings indicate the coronavirus RdRp complex is an Achilles heel and support nucleoside analogues as candidates for COVID-19 treatment.