β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside tri-phosphate form and concentrate in genomes of RNA viruses during viral replication. beta-D-N-4-hydroxycridine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.

Automated summary

Mutagenic ribonucleosides can serve as broad-spectrum antiviral agents, but may pose risks to the host due to their host mutagenic activity in addition to antiviral activity.