Proceedings of the National Academy of Sciences of the United States of AmericaAdenosine MonophosphateAlanineSARS-CoV-2Antiviral AgentsHumans
Molecular basis of SARS-CoV-2 proofreading enzyme-mediated resistance to remdesivir.
Yang Yang, Yu Li, Scott T Becker, Ayesha Khan, Gloria Luo, Bin Liu, Chang Liu
Published: 202510.1073/pnas.2519755122
Abstract
Open AccessSARS-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.