Effects of Antiviral Nucleoside Analogues on the Maintenance of the Mitochondrial Genome

Abstract

The outbreak of the COVID‐19 pandemic prompted the search for effective antivirals. Remdesivir (Gilead Sciences) was the first nucleoside analogue approved by the FDA for COVID‐19 treatment, and currently the FDA considers authorization for the use of another analogue, molnupiravir (Merck). Mitochondrial toxicity, resulting from the interference with mitochondrial DNA (mtDNA) replication, is the most common side effect of nucleoside analogues treatment. In addition, defects to the mtDNA synthesis may give rise to heritable mutations, which may be carried undetected for generations before populating mitochondria to the level that onsets a mitochondrial disease. Therefore, nucleoside analogues need to be thoroughly investigated for their impact on the maintenance and integrity of the mitochondrial genome. We recently assessed the effect of remdesivir on the maintenance of the mitochondrial genome. We observed that in in vitro DNA synthesis assays, its triphosphate metabolite may impede the synthetic activity of the mitochondrial replicative polymerase, Pol γ, when in excess over nucleotides. Prompted by this finding, we tested the effect of the nucleoside metabolite of remdesivir on the maintenance and integrity of the mitochondrial genome in proliferating fibroblasts. However, we found no evidence for deleterious effects on the integrity of the mitochondrial genome. We are currently performing an analogical assessment of the effects of molnupiravir on the integrity of the mitochondrial genome. Thus far, we have observed that, unlike remdesivir, molnupiravir is cytotoxic for proliferating fibroblasts and results in a decrease in mtDNA copy number. We are currently testing the impact of molnupiravir on the activity of Pol γ in vitro, and its potential to elicit mutations in the mitochondrial genome in vivo.