Molecular basis of SARS-CoV-2 proofreading enzyme-mediated resistance to remdesivir.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41032524.
- Also identified by DOI 10.1073/pnas.2519755122 and PMC identifier 12519199.
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Abstract
SARS-CoV-2's remarkable resistance to nucleotide analog antivirals such as remdesivir, which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies. We reveal that remdesivir incorporation destabilizes RdRp-RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses. These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance.
Medical subject headings
- Adenosine Monophosphate
- Alanine
- SARS-CoV-2
- Antiviral Agents
- Drug Resistance, Viral
- Exoribonucleases