Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir
Waters et al.
, Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the..
, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471 (Review)
Review of antiviral nucleoside analog drugs that induce lethal mutagenesis, including molnupiravir and favipiravir, and the potential mutagenic risks to human DNA and human mitochondrial DNA. Author recommends monitoring for mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity.
Waters et al., 28 Jan 2022, USA, peer-reviewed, 5 authors.
Abstract: Received: 30 October 2021
Revised: 28 December 2021
Accepted: 8 January 2022
Human genetic risk of treatment with antiviral nucleoside
analog drugs that induce lethal mutagenesis: the special
case of molnupiravir
Michael D. Waters1
Stafford Warren2 |
Michael Waters Consulting USA,
Hillsborough, North Carolina, USA
Anne Arundel Medical Center, Annapolis,
| Philip Lewis4
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
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.
Michael D. Waters, Michael Waters Consulting
USA, Hillsborough, North Carolina, USA.
“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
nupiravir on the basis of all available information and focus on the need for additional
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.
5-(2-chloroethyl)-20 -deoxyuridine, COVID-19 pandemic, favipiravir, molnupiravir, ribavirin,
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...
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