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Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms.
Stevens, Laura J; Pruijssers, Andrea J; Lee, Hery W; Gordon, Calvin J; Tchesnokov, Egor P; Gribble, Jennifer; George, Amelia S; Hughes, Tia M; Lu, Xiaotao; Li, Jiani; Perry, Jason K; Porter, Danielle P; Cihlar, Tomas; Sheahan, Timothy P; Baric, Ralph S; Götte, Matthias; Denison, Mark R.
  • Stevens LJ; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Pruijssers AJ; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Lee HW; Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, USA.
  • Gordon CJ; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2T9, Canada.
  • Tchesnokov EP; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2T9, Canada.
  • Gribble J; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2T9, Canada.
  • George AS; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Hughes TM; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Lu X; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Li J; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Perry JK; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Porter DP; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Cihlar T; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Sheahan TP; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Baric RS; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Götte M; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Denison MR; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton AB T6G 2T9, Canada.
Sci Transl Med ; 14(656): eabo0718, 2022 08 03.
Article in English | MEDLINE | ID: covidwho-1816673
ABSTRACT
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 is critical to understand factors that promote or prevent RDV resistance. We passaged SARS-CoV-2 in the presence of increasing concentrations of GS-441524, the parent nucleoside of RDV. After 13 passages, we isolated three viral lineages with phenotypic resistance as defined by increases in half-maximal effective concentration from 2.7- to 10.4-fold. Sequence analysis identified nonsynonymous mutations in nonstructural protein 12 RNA-dependent RNA polymerase (nsp12-RdRp) V166A, N198S, S759A, V792I, and C799F/R. Two lineages encoded the S759A substitution at the RdRp Ser759-Asp-Asp active motif. In one lineage, the V792I substitution emerged first and then combined with S759A. Introduction of S759A and V792I substitutions at homologous nsp12 positions in murine hepatitis virus demonstrated transferability across betacoronaviruses; introduction of these substitutions resulted in up to 38-fold RDV resistance and a replication defect. Biochemical analysis of SARS-CoV-2 RdRp encoding S759A demonstrated a roughly 10-fold decreased preference for RDV-triphosphate (RDV-TP) as a substrate, whereas nsp12-V792I diminished the uridine triphosphate concentration needed to overcome template-dependent inhibition associated with RDV. The in vitro-selected substitutions identified in this study were rare or not detected in the greater than 6 million publicly available nsp12-RdRp consensus sequences in the absence of RDV selection. The results define genetic and biochemical pathways to RDV resistance and emphasize the need for additional studies to define the potential for emergence of these or other RDV resistance mutations in clinical settings.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA-Dependent RNA Polymerase / Drug Resistance, Viral / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Sci Transl Med Journal subject: Science / Medicine Year: 2022 Document Type: Article Affiliation country: Scitranslmed.abo0718

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / RNA-Dependent RNA Polymerase / Drug Resistance, Viral / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Sci Transl Med Journal subject: Science / Medicine Year: 2022 Document Type: Article Affiliation country: Scitranslmed.abo0718