Abstract: Received: 30 October 2021 Revised: 28 December 2021 Accepted: 8 January 2022 DOI: 10.1002/em.22471 REVIEW Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir Michael D. Waters1 Fengyu Zhang5 | Stafford Warren2 | 1 Michael Waters Consulting USA, Hillsborough, North Carolina, USA 2 Anne Arundel Medical Center, Annapolis, Maryland, USA 3 Claude Hughes3 | Philip Lewis4 | Abstract This review considers antiviral nucleoside analog (NA) drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV Duke University Medical Center, Durham, North Carolina, USA or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that 4 Cornell University, Ithaca, New York, USA molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or Global Clinical and Translational Research Institute, Bethesda, Maryland, USA favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Correspondence Michael D. Waters, Michael Waters Consulting USA, Hillsborough, North Carolina, USA. Email: mdwaters@centurylink.net; mdwatersalt@gmail.com “host” cell mutagenicity of its active principle, β-d-N4-hydroxycytidine, we have This article was submitted to Environmental and Molecular Mutagenesis on October 30, 2021. The same article was submitted to Authorea on November 4, 2021, for publication as a preprint and was assigned DOI: 10.22541/au.163603698.81246011/v1. nupiravir on the basis of all available information and focus on the need for additional 5 Because of its anticipated global use, its relative potency, and the reported in vitro reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-20 -deoxyuridine. We consider the potential genetic risks of molhuman genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis. KEYWORDS 5-(2-chloroethyl)-20 -deoxyuridine, COVID-19 pandemic, favipiravir, molnupiravir, ribavirin, β-d-N4-hydroxycytidine 1 | I N T RO DU CT I O N uncertainties such that all aspects, and especially safety evaluation, require caution. The degree to which the precautionary principle The conduct of human clinical trials in the complex and ever-changing should or should not be applied to potential life-saving pharmaceuti- COVID-19 pandemic means that any study may be fraught with cals is a significant genetic and translational toxicology challenge. In Environ Mol Mutagen...