Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms

• DOI: 10.1126/scitranslmed.abo0718
• Publication Date: 2022-04-28T18:02:29Z
• Authors: Laura J. Stevens; Andrea J. Pruijssers; Hery W. Lee; Calvin J. Gordon; Egor P. Tchesnokov; Jennifer Gribble; Amelia S. George; Tia M. Hughes; Xiaotao Lu; Jiani Li; Jason K. Perry; Danielle P. Porter; Tomas Cihlar; Timothy P. Sheahan; Ralph S. Baric; Matthias Götte; Mark R. Denison
• Keywords: Coronaviridae; Nonsynonymous substitution; Coronavirus

The nucleoside analog remdesivir (RDV) is a Food and Drug Administration-approved antiviral for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Thus, it critical to understand factors that promote or prevent RDV resistance. We passaged SARS-CoV-2 in the presence increasing concentrations GS-441524, parent RDV. After 13 passages, we isolated three viral lineages with phenotypic resistance as defined by increases half-maximal effective concentration from 2.7- 10.4-fold. Sequence analysis identified nonsynonymous mutations nonstructural protein 12 RNA-dependent RNA polymerase (