Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused by the Arabinosides and Anti-COVID-19 drugs
, M., Dec 2024
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 increased risk of acute kidney injury, Leo, Briciu, Muntean, Petrov show increased risk of liver injury, and Negru, Cheng, Mohammed show increased risk of cardiac disorders with remdesivir.
Study covers molnupiravir and remdesivir.
1.
Gérard et al., Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2145.
2.
Zhou et al., Acute Kidney Injury and Drugs Prescribed for COVID-19 in Diabetes Patients: A Real-World Disproportionality Analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2022.833679.
3.
Wu et al., Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS, Frontiers in Pharmacology, doi:10.3389/fphar.2022.692828.
4.
Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.
5.
Choi et al., Comparative effectiveness of combination therapy with nirmatrelvir–ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir–ritonavir in patients hospitalised with COVID-19: a target trial emulation study, The Lancet Infectious Diseases, doi:10.1016/S1473-3099(24)00353-0.
6.
Kim et al., Investigating the Safety Profile of Fast‐Track COVID‐19 Drugs Using the FDA Adverse Event Reporting System Database: A Comparative Observational Study, Pharmacoepidemiology and Drug Safety, doi:10.1002/pds.70043.
7.
Leo et al., Hepatocellular liver injury in hospitalized patients affected by COVID-19: Presence of different risk factors at different time points, Digestive and Liver Disease, doi:10.1016/j.dld.2021.12.014.
8.
Briciu et al., Evolving Clinical Manifestations and Outcomes in COVID-19 Patients: A Comparative Analysis of SARS-CoV-2 Variant Waves in a Romanian Hospital Setting, Pathogens, doi:10.3390/pathogens12121453.
9.
Muntean et al., Effects of COVID-19 on the Liver and Mortality in Patients with SARS-CoV-2 Pneumonia Caused by Delta and Non-Delta Variants: An Analysis in a Single Centre, Pharmaceuticals, doi:10.3390/ph17010003.
10.
Petrov et al., The Effect of Potentially Hepatotoxic Medicinal Products on Alanine Transaminase Levels in COVID-19 Patients: A Case–Control Study, Safety and Risk of Pharmacotherapy, doi:10.30895/2312-7821-2025-458.
11.
Negru et al., Comparative Pharmacovigilance Analysis of Approved and Repurposed Antivirals for COVID-19: Insights from EudraVigilance Data, Biomedicines, doi:10.3390/biomedicines13061387.
Rahman et al., 20 Dec 2024, peer-reviewed, 1 author.
Elucidation of the DNA repair mechanisms involved in the repair of DNA damage caused
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