Oxidative DNA Damage by N(4)-hydroxycytidine, a Metabolite of the SARS-CoV-2 Antiviral Molnupiravir

Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N(4)-hydroxycytidine (NHC), a molnupiravir metabolite, treated with cytidine deaminase (CDA) induced Cu(II)-mediated oxidative DNA damage in isolated DNA. A colorimetric assay...

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Detalles Bibliográficos
Autores principales: Kobayashi, Hatasu, Mori, Yurie, Ahmed, Sharif, Hirao, Yuichiro, Kato, Shinya, Kawanishi, Shosuke, Murata, Mariko, Oikawa, Shinji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Brief Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132762/
https://www.ncbi.nlm.nih.gov/pubmed/36461940
http://dx.doi.org/10.1093/infdis/jiac477
Descripción
Sumario:Molnupiravir is an antiviral agent recently used for treating coronavirus disease 2019 (COVID-19). Here, we demonstrate that N(4)-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 H(2)O(2) 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.

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