Oxidative DNA Damage by N4-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir

J Infect Dis. 2023 Apr 26;227(9):1068-1072. doi: 10.1093/infdis/jiac477.

Abstract

Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N4-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay revealed hydroxylamine generation from CDA-treated NHC. The site specificity of DNA damage also suggested involvement of hydroxylamine in the damage. Furthermore, Cu(I) and H2O2 play an important role in the DNA damage. We propose oxidative DNA damage via CDA-mediated metabolism as a possible mutagenic mechanism of NHC, highlighting the need for careful risk assessment of molnupiravir use in therapies for viral diseases, including COVID-19.

Keywords: N 4-hydroxycytidine; 8-dihydro-2′-deoxyguanosine; 8-oxo-7; DNA damage; cytidine deaminase; hydroxylamine; molnupiravir; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents* / pharmacology
  • Antiviral Agents* / therapeutic use
  • COVID-19*
  • DNA Damage
  • Humans
  • Hydrogen Peroxide
  • Hydroxylamines / pharmacology
  • Oxidative Stress
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • molnupiravir
  • N(4)-hydroxycytidine
  • Hydrogen Peroxide
  • Hydroxylamines