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Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: The special case of molnupiravir.
Waters, Michael D; Warren, Stafford; Hughes, Claude; Lewis, Philip; Zhang, Fengyu.
Affiliation
  • Waters MD; Michael Waters Consulting USA, Hillsborough, North Carolina, USA.
  • Warren S; Anne Arundel Medical Center, Annapolis, Maryland, USA.
  • Hughes C; Duke University Medical Center, Durham, North Carolina, USA.
  • Lewis P; Cornell University, Ithaca, New York, USA.
  • Zhang F; Global Clinical and Translational Research Institute, Bethesda, Maryland, USA.
Environ Mol Mutagen ; 63(1): 37-63, 2022 01.
Article in En | MEDLINE | ID: mdl-35023215
This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, ß-d-N4-hydroxycytidine, we have 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)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / DNA Damage / Cytidine / SARS-CoV-2 / COVID-19 Drug Treatment / Hydroxylamines / Nucleosides Type of study: Etiology_studies / Risk_factors_studies Limits: Humans Language: En Journal: Environ Mol Mutagen Journal subject: BIOLOGIA MOLECULAR / SAUDE AMBIENTAL Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Antiviral Agents / DNA Damage / Cytidine / SARS-CoV-2 / COVID-19 Drug Treatment / Hydroxylamines / Nucleosides Type of study: Etiology_studies / Risk_factors_studies Limits: Humans Language: En Journal: Environ Mol Mutagen Journal subject: BIOLOGIA MOLECULAR / SAUDE AMBIENTAL Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States