Molnupiravir: coding for catastrophe

Malone et al., Nature Structural & Molecular Biology, doi:10.1038/s41594-021-00657-8

Sep 2021

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Review of recent studies on molnupiravir's mechanism of lethal mutagenesis. Authors note that potential off-target effects require further investigation, because molnupiravir may be mutagenic to host DNA during host DNA replication.

Reviews covering molnupiravir for COVID-19 include1-9.

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1. Bacigalupo et al., Unveiling patenting strategies of therapeutics and vaccines: evergreening in the context of COVID-19 pandemic, Frontiers in Medicine, doi:10.3389/fmed.2023.1287542.frontiersin.org, doi.org.

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

3. Boretti, A., On the choice of Molnupiravir and Paxlovid as the only antivirals permitted for COVID-19 infection in Australia, Clinical and Experimental Medicine, doi:10.1007/s10238-023-01010-7.springer.com, doi.org.

4. 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.

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

6. 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.

7. Anonymous, Treating a Pandemic Respiratory Disease with a Mutagen is a Doomsday Scenario, Authorea, doi:10.22541/au.163854323.34557301/v1.authorea.com, doi.org.

8. Goldstein, L., Molnupiravir: mutagenic, carcinogenic, authorized in the UK, TrialSite News, trialsitenews.com/molnupiravir-mutagenic-carcinogenic-authorized-in-the-uk/.trialsitenews.com.

9. Malone et al., Molnupiravir: coding for catastrophe, Nature Structural & Molecular Biology, doi:10.1038/s41594-021-00657-8.nature.com, doi.org.

Malone et al., 13 Sep 2021, peer-reviewed, 2 authors.

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Antiviral Therapeutics, Brandon Malone, Elizabeth A Campbell

Molnupiravir: coding for catastrophe Molnupiravir, a wide-spectrum antiviral that is currently in phase 2/3 clinical trials for the treatment of COVID-19, is proposed to inhibit viral replication by a mechanism known as 'lethal mutagenesis'. Two recently published studies reveal the biochemical and structural bases of how molnupiravir disrupts the fidelity of SARS-CoV-2 genome replication and prevents viral propagation by fostering error accumulation in a process referred to as 'error catastrophe'.

Competing interests The authors declare no competing interests. Is it a wrap? Nucleosome interactions of the BRCA1-binding partner, BARD1, steal the scene emerging findings provide compelling evidence that the bRCA1-binding partner bARD1 contributes yet further to bRCA1 function. bARD1 is crucial for positioning the e2 ubiquitin-conjugating enzyme that confers specificity of its ligase to residues on histone H2A, and bARD1 also promotes DNA damage-induced chromatin recruitment through an interaction with ubiquitin-conjugated Lys13 or Lys15 of H2A on the nucleosome core particle. Nature Joanna R. Morris T he BRCA1-BARD1 complex is a crucial tumor suppressor that is linked to the prevention of familial breast and ovarian cancers. The heterodimer has several proposed functions, including the regulation of DNA resection and the promotion of RAD51 loading through PALB2-BRCA2, which is required for homology-directed DNA repair. Despite the tremendous focus in the decades since the discovery of the BRCA1 gene, several critical questions have remained, if not completely unanswered, then with unsatisfactory solutions. Although a complete literature review is not possible here, some pertinent observations are that recruitment of BRCA1-BARD1 to damaged chromatin occurs through the

References

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Bouvet, Proc. Natl Acad. Sci

Gordon, None, J. Biol. Chem

Gordon, Tchesnokov, Schinazi, Götte, None, J. Biol. Chem

Hall, None, J. Infect. Dis, doi:10.1093/infdis/jiab305

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Kabinger, None, Nat. Struct. Mol. Biol, doi:10.1038/s41594-021-00651-0

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Sticher, None, Antimicrob. Agents Chemother

Toots, None, Sci. Transl. Med

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Vicenti, Zazzi, Saladini, None, Expert Opin. Ther. Pat

Wahl, None, Nature

Yoon, None, Antimicrob. Agents Chemother

Zhou, None, J. Infect. Dis, doi:10.1093/infdis/jiab2

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