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

Favipiravir, a SARS-CoV-2 and other RNA viruses replication inhibitor, is a guanosine analogue that acts as elongation terminator for viral RNA-dependent RNA polymerase (RdRp), whose effect results in the production of highly mutated viral genomes. Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis for SARS-CoV-2. SARS-CoV-2 nsp12 complex with nsp7 and 8 is viral RdRp, and is targeted by Favipiravir. The RNA elongation activity of SARS-CoV-2 RdRp is very rapid, which increases the frequency of nucleotide misincorporation. Although SARS-CoV-2 possesses exonuclease for proofreading, the rapid elongation and error frequency results in the efficiency of Favipiravir that acts as mutation generator.