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Updated: Jan 16, 2026

Reverse Genetics to Engineer Positive-Sense RNA Virus Variants
Published on: June 9, 2022
Molecular basis of SARS-CoV-2 proofreading enzyme-mediated resistance to remdesivir
Yang Yang1, Yu Li1, Scott T Becker1
1Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011.
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.
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