β-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells
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Updated: Nov 6, 2025
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Shuntai Zhou1, Collin S Hill1, Sanjay Sarkar2
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Abstract:
Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. β-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.
Insights
Highly active mutagenic ribonucleosides, like molnupiravir
Area of Science:
- Virology and antiviral drug development.
- Molecular biology and mutagenesis.
Background:
- Mutagenic ribonucleosides are explored as broad-spectrum antiviral agents.
- These compounds are converted to active triphosphate forms, incorporating into viral RNA genomes.
- Molnupiravir's metabolite, β-d-N4-hydroxycytidine (NHC), shows potent activity against SARS-CoV-2.
Purpose of the Study:
- To compare the antiviral efficacy of NHC with other agents like ribavirin and favipiravir.
- To investigate the correlation between antiviral activity and RNA mutagenesis.
- To assess the potential host mutational risks associated with NHC.
Main Methods:
- Antiviral activity assays against SARS-CoV-2.
- Measurement of mutagenesis in viral RNA.
- Host cell culture assays to detect mutational activity.
Main Results:
- NHC demonstrated over 100-fold greater activity than ribavirin or favipiravir against SARS-CoV-2.
- Antiviral efficacy correlated directly with the level of mutagenesis in the viral RNA.
- NHC exhibited host mutational activity in cell culture, suggesting shared metabolic pathways with host nucleic acid precursors.
Conclusions:
- NHC is a highly potent mutagenic ribonucleoside antiviral agent.
- The mechanism involves significant RNA mutagenesis.
- High mutagenic potential in antiviral agents may pose risks to the host.
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