Molnupiravir; molecular and functional descriptors of mitochondrial safety

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Molnupiravir is an orally active nucleoside analog antiviral drug that recently was approved by the U.S. FDA for emergency treatment of adult patients infected with the SARS-CoV-2 (COVID-19) virus and at risk for severe progression. The active form of the drug, N-hydroxycytidine (NHC) triphosphate competes for incorporation by RNA-dependent RNA-polymerase (RdRp) into the replicating viral genome resulting in mutations and arrest of the replicating virus. Historically, some nucleoside analog antiviral drugs have been found to lack specificity for the virus and also inhibit replication and/or expression of the mitochondrial genome. The objective of the present study was to test whether molnupiravir and/or NHC also target mitochondrial DNA polymerase gamma (PolG) or RNA polymerase (POLRMT) activity to inhibit the replication and/or expression of the mitochondrial genome leading to impaired mitochondrial function. Human-derived HepG2 cells were exposed for 48 h in culture to increasing concentrations of either molnupiravir or NHC after which cytotoxicity, mtDNA copy number and mitochondrial gene expression were determined. The phenotypic endpoint, mitochondrial respiration, was measured with the Seahorse® XF96 Extracellular Flux Analyzer. Both molnupiravir and NHC were cytotoxic at concentrations of ≥10 μM. However, at non-cytotoxic concentrations, neither significantly altered mitochondrial gene dose or transcription, or mitochondrial respiration. From this we conclude that mitochondrial toxicity is not a primary off target in the mechanism of cytotoxicity for either molnupiravir or its active metabolite NHC in the HepG2 cell line.

Original languageEnglish (US)
Article number116003
JournalToxicology and Applied Pharmacology
StatePublished - May 1 2022

Bibliographical note

Funding Information:
This work was supported in-part by an unrestricted research grant from the 3M Company . 3M Company did not contribute to the study concept or participate in any part of the experimental design, data analysis and interpretation, or in preparation of this manuscript. The authors declare no conflict of interest with regard to funding or correspondence with the manufacturer of the drug prior to or during the conduct and publication of this investigation.

Publisher Copyright:
© 2022 Elsevier Inc.


  • Covid-19
  • Mitochondria
  • Molnupiravir

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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