Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused by the Arabinosides and Anti-COVID-19 drugs

In Vitro study showing potential genotoxic side effects of remdesivir and molnupiravir linked to DNA repair pathway deficiencies. Remdesivir incorporation into nascent DNA caused replication fork stalling and acute S-phase arrest in FEN1-deficient cells, impairing Okazaki fragment maturation and amplifying DNA damage. Molnupiravir, which integrates into RNA but requires PARP1, TDP2, BRCA2, and ATM for host DNA repair, exhibited heightened cytotoxicity in cells lacking these factors, suggesting BRCA2-mutated individuals may face elevated risks. Both drugs showed dependency on distinct repair mechanisms, with remdesivir relying on FEN1 for replication fidelity and molnupiravir requiring homologous recombination and BER-independent PARP1 activity. These findings highlight context-dependent risks, particularly in patients with compromised DNA repair pathways, compared to other antivirals with lower genomic integration potential.

Gérard, Zhou, Wu, Kamo, Choi, Kim show significantly increased risk of acute kidney injury with remdesivir.