Reader Comment on: “Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir”

Frederick et al., Toxicological Sciences, doi:10.1093/toxsci/kfae156

Dec 2024

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Commentary on Escobar et al. regarding the genotoxicity and carcinogenicity of molnupiravir, raising concerns that the study did not adequately address the potential for molnupiravir's active metabolite to be incorporated into cellular DNA and cause mutations. Authors argue the cell and animal models used lacked sensitivity to detect the mutagenic potential, and point to concerning signals in the reported data that warrant further investigation.

Potential risks of molnupiravir include the creation of dangerous variants, and mutagenicity, carcinogenicity, teratogenicity, and embryotoxicity2-15. Multiple analyses have identified variants potentially created by molnupiravir16-20.

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1. Escobar et al., Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir, Toxicological Sciences, doi:10.1093/toxsci/kfae112.oup.com, doi.org.

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

3. 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.

4. Shum, C., An investigational study into the drug-associated mutational signature in SARS-CoV-2 viruses, The University of Hong Kong, PhD Thesis, hub.hku.hk/handle/10722/344396.hku.hk.

5. 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.

6. 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.

7. 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.

8. Shiraki et al., Convenient screening of the reproductive toxicity of favipiravir and antiviral drugs in Caenorhabditis elegans, Heliyon, doi:10.1016/j.heliyon.2024.e35331.sciencedirect.com, doi.org.

9. Gruber et al., Molnupiravir increases SARS‐CoV‐2 genome diversity and complexity: A case‐control cohort study, Journal of Medical Virology, doi:10.1002/jmv.29642.wiley.com, doi.org.

10. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

11. Rahman, M., Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused by the Arabinosides and Anti-COVID-19 drugs, tokyo-metro-u.repo.nii.ac.jp/records/2000972.ac.jp.

12. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

13. Chamod et al., Molnupiravir Metabolite--N4-hydroxycytidine Causes Cytotoxicity and DNA Damage in Mammalian Cells in vitro: N4-hydroxycytidine Induced Cytotoxicity DNA Damage, Asian Medical Journal and Alternative Medicine, 23:3, asianmedjam.com/index.php/amjam/article/view/1448.asianmedjam.com.

14. Standing et al., Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients, Nature Communications, doi:10.1038/s41467-024-45641-0.nature.com, doi.org.

15. Mori et al., Reactive oxygen species-mediated cytotoxic and DNA-damaging mechanism of N4-hydroxycytidine, a metabolite of the COVID-19 therapeutic drug molnupiravir, Free Radical Research, doi:10.1080/10715762.2025.2469738.tandfonline.com, doi.org.

16. Focosi et al., The fitness of molnupiravir-signed SARS-CoV-2 variants: imputation analysis based on prescription counts and GISAID analyses by country, Intervirology, doi:10.1159/000540282.karger.com, doi.org.

17. Sanderson et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature, doi:10.1038/s41586-023-06649-6.nature.com, doi.org.

18. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

19. Kosakovsky Pond et al., Anti-COVID drug accelerates viral evolution, Nature, doi:10.1038/d41586-023-03248-3.nature.com, doi.org.

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

Frederick et al., 18 Dec 2024, peer-reviewed, 3 authors.

This Paper Molnupiravir All

Reader comment on: "Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir"

Clay B Frederick, Raymond F Schinazi, Ronald Swanstrom

doi:10.1093/toxsci/kfae156/7927843

We read with interest the recent paper addressing the potential genotoxicity and carcinogenicity of molnupiravir in treated coronavirus disease 2019 (COVID-19) patients (Escobar et al. 2024) . Molnupiravir is a prodrug that releases the nucleoside analog ß-D-N 4 -hydroxycytidine (NHC) in vivo. NHC is incorporated into the viral RNA genome, and it inhibits the virus by "lethal mutagenesis." Our concern is that a portion of the released NHC may be distributed to tissues with dividing cells where it may be phosphorylated and reduced by ribonucleotide reductase to form 2 0deoxy-NHC-5 0 -triphosphate (dNHC-TP) which may be incorporated into newly synthesized DNA resulting in the introduction of point mutations. The incorporation of NHC into cellular DNA, and its resulting mutagenicity has been described in bacteria and mammalian cells in many in vitro studies. As described below, the information provided by Escobar et al. did little to alleviate this concern

References

Escobar, Sobol, Miller, Ferry-Martin, Stermer et al., Comprehensive genotoxicity and carcinogenicity assessment of molnupiravir, doi:10.1093/toxsci/kfae112

Painter, Bowen, Bluemling, Debergh, Edpuganti et al., The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection, Antiviral Res, doi:10.1016/j.antiviral.2019.104597

Shemansky, Mcdaniel, Klimas, Dertinger, Dobrovolsky et al., Pig-a gene mutation database, Environ Mol Mutagenesis

Skopek, Kort, Marino, Relative sensitivity of the endogenous hprt gene and lacI transgene in ENU-treated Big Blue B6C3F1 mice, Environ Mol Mutagen

Zhou, Hill, Woodburn, Schinazi, Swanstrom, Letter to the editor: reply to Troth et al, J Infect Dis, doi:10.1093/infdis/jiab363

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