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

J Infect Dis. 2021 Aug 2;224(3):415-419. doi: 10.1093/infdis/jiab247.

Abstract

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. β-d-N4-hydroxycytidine (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.

Keywords: NHC; SARS-CoV-2; molnupiravir; mutagenicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacology*
  • CHO Cells / drug effects
  • Cells, Cultured
  • Cricetulus
  • Cytidine / adverse effects
  • Cytidine / analogs & derivatives*
  • Cytidine / pharmacology
  • Dose-Response Relationship, Drug
  • Mutagenesis / drug effects
  • Mutagens / adverse effects
  • Mutagens / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / genetics
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Mutagens
  • Cytidine
  • N(4)-hydroxycytidine