Evaluation of the mutagenic effects of Molnupiravir and N4-hydroxycytidine in bacterial and mammalian cells by HiFi sequencing

Miranda et al., Environmental and Molecular Mutagenesis, doi:10.1002/em.22510

Oct 2022

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In Vitro genotoxocity study of molnupiravir showing dose dependent increased genome-wide mutation frequencies with mouse lymphoma L5178Y and human lymphoblastoid TK6 cells.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Hadj Hassine, Huntsman, Swanstrom, Waters, Zibat. Multiple analyses have identifed variants potentially created by molnupiravir Fountain-Jones, Sanderson, twitter.com.

1. Fountain-Jones et al., Antiviral treatments lead to the rapid accrual of hundreds of SARS-CoV-2 mutations in immunocompromised patients, medRxiv, doi:10.1101/2022.12.21.22283811.medrxiv.org, doi.org.

2. Hadj Hassine et al., Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity, Viruses, doi:10.3390/v14040841.mdpi.com, doi.org.

3. Huntsman, M., An assessment of the reproductive toxicity of the anti-COVID-19 drug molnupiravir using stem cell-based embryo models, Master's Thesis, scholarspace.manoa.hawaii.edu/items/cd11342c-b4dc-44c0-8b44-ce6e3369c40b.hawaii.edu.

4. Sanderson et al., Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases, medRxiv, doi:10.1101/2023.01.26.23284998.medrxiv.org, doi.org.

5. Swanstrom et al., Lethal mutagenesis as an antiviral strategy, Science, doi:10.1126/science.abn0048.science.org, doi.org.

6. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

7. Waters et al., Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: the special case of molnupiravir, Environmental and Molecular Mutagenesis, doi:10.1002/em.22471.wiley.com, doi.org.

8. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

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Miranda et al., 1 Oct 2022, peer-reviewed, 4 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

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