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Proc Natl Acad Sci U S A
. 2025 Oct 7;122(40):e2519755122.
doi: 10.1073/pnas.2519755122. Epub 2025 Oct 1. Molecular basis of SARS-CoV-2 proofreading enzyme-mediated resistance to remdesivir
Yang Yang 1 , Yu Li 1 , Scott T Becker 1 , Ayesha Khan 1 , Gloria Luo 2 , Bin Liu 3 , Chang Liu 2
Affiliations
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.
Keywords: coronavirus; cryo-EM; drug resistance; proofreading; remdesivir.
. 2025 Oct 7;122(40):e2519755122.
doi: 10.1073/pnas.2519755122. Epub 2025 Oct 1. Molecular basis of SARS-CoV-2 proofreading enzyme-mediated resistance to remdesivir
Yang Yang 1 , Yu Li 1 , Scott T Becker 1 , Ayesha Khan 1 , Gloria Luo 2 , Bin Liu 3 , Chang Liu 2
Affiliations
- PMID: 41032524
- DOI: 10.1073/pnas.2519755122
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.
Keywords: coronavirus; cryo-EM; drug resistance; proofreading; remdesivir.