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Proc Natl Acad Sci U S A . Molecular basis of SARS-CoV-2 proofreading enzyme-mediated resistance to remdesivir

tetano

tetano

Editor, Senior Moderator
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[SUP] 1 [/SUP], Yu Li[SUP] 1 [/SUP], Scott T Becker[SUP] 1 [/SUP], Ayesha Khan[SUP] 1 [/SUP], Gloria Luo[SUP] 2 [/SUP], Bin Liu[SUP] 3 [/SUP], Chang Liu[SUP] 2 [/SUP]



Affiliations
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.

Keywords: coronavirus; cryo-EM; drug resistance; proofreading; remdesivir.

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