Molecular Basis of SARS-CoV-2 Proofreading Enzyme Resistance to Remdesivir

@article{0590ccd01d58496c83efc2fa7f867f64,

title = “Molecular basis of SARS-CoV-2 proofreading enzyme–mediated resistance to remdesivir”,

abstract = “SARS-CoV-2{textquoteright}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”,

author = “Yang Yang and Yu Li and Becker, {Scott T.} and Ayesha Khan and Gloria Luo and Bin Liu and Chang Liu”,

note = “Publisher Copyright: Copyright {textcopyright} 2025 the Author(s).”,

year = “2025”,

month = oct,

doi = “10.1073/pnas.2519755122”,

language = “English (US)”,

volume = “122”,

journal = “Proceedings of the National Academy of Sciences of the United States of America”,

issn = “0027-8424”,

publisher = “National Academy of Sciences”,

number = “40”,

}