Remdesivir; molecular and functional measures of mitochondrial safety

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Remdesivir is one of a few antiviral drugs approved for treating severe cases of coronavirus 2 (SARS-CoV-2) infection in hospitalized patients. The prodrug is a nucleoside analog that interferes with viral replication by inhibiting viral RNA-dependent RNA polymerase. The drug has also been shown to be a weak inhibitor of human mitochondrial RNA polymerase, leaving open the possibility of mitochondrial off-targets and toxicity. The investigation was designed to explore whether remdesivir causes mitochondrial toxicity, using both genomic and functional parameters in the assessment. Human-derived HepG2 liver cells were exposed for up to 48 h in culture to increasing concentrations of remdesivir. At sub-cytotoxic concentrations (<1 μM), the drug failed to alter either the number of copies or the expression of the mitochondrial genome. mtDNA copy number was unaffected as was the relative rates of expression of mtDNA-encoded and nuclear encoded subunits of complexes I and IV of the mitochondrial respiratory chain. Consistent with this is the observation that remdesivir was without effect on mitochondrial respiration, including basal respiration, proton leak, maximum uncoupled respiration, spare respiratory capacity or coupling efficiency. We conclude that although remdesivir has weak inhibitory activity towards mitochondrial RNA polymerase, mitochondria are not primary off-targets for the mechanism of cytotoxicity of the drug.

Original languageEnglish (US)
Article number115783
JournalToxicology and Applied Pharmacology
Volume433
DOIs
StatePublished - Dec 15 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • COVID
  • Mitochondria
  • Off-Target
  • Remdesivir

Fingerprint

Dive into the research topics of 'Remdesivir; molecular and functional measures of mitochondrial safety'. Together they form a unique fingerprint.

Cite this