Using error-corrected sequencing for evaluating mutagenicity of molnupiravir in humans.

Area of Science:

• Virology
• Genetics
• Pharmacology

Background:

• Molnupiravir (MOV) is an oral prodrug of N-hydroxycytidine (NHC), used to treat SARS-CoV-2 infections.
• While MOV and NHC show mutagenicity in cell cultures, in vivo data have been inconclusive.
• A novel error-corrected sequencing (ECS) method was developed to detect mutations in human tissue samples.

Purpose of the Study:

• To assess the in vivo mutagenicity of Molnupiravir in patients treated for COVID-19.
• To compare mutation frequencies and spectra in patients who received MOV versus a matched control group.

Main Methods:

• Recruited two groups of COVID-19 patients: one treated with MOV, one not (matched controls).
• Utilized a validated error-corrected sequencing (ECS) method to analyze basepair substitutions in peripheral blood nucleated cells.
• Compared mutation frequencies, types, and spectra between the MOV and control groups.

Main Results:

• No significant differences in mutation frequency, types, or spectra were observed between the MOV and control groups.
• The mutational spectra in the MOV group did not exhibit signatures expected from MOV or NHC exposure based on cell culture data.
• The study found no evidence of mutagenic consequences from the authorized dose of Molnupiravir.

Conclusions:

• The authorized dose of Molnupiravir for COVID-19 treatment does not appear to cause detectable mutations in patients.
• The developed ECS method is a valuable tool for assessing in vivo mutagenesis in various experimental settings.