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Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Kabinger, Florian; Stiller, Carina; Schmitzová, Jana; Dienemann, Christian; Kokic, Goran; Hillen, Hauke S; Höbartner, Claudia; Cramer, Patrick.
  • Kabinger F; Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
  • Stiller C; Universität Würzburg, Lehrstuhl für Organische Chemie I, Würzburg, Germany.
  • Schmitzová J; Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
  • Dienemann C; Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
  • Kokic G; Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
  • Hillen HS; University Medical Center Göttingen, Department of Cellular Biochemistry, Göttingen, Germany.
  • Höbartner C; Max Planck Institute for Biophysical Chemistry, Research Group Structure and Function of Molecular Machines, Göttingen, Germany.
  • Cramer P; Universität Würzburg, Lehrstuhl für Organische Chemie I, Würzburg, Germany. claudia.hoebartner@uni-wuerzburg.de.
Nat Struct Mol Biol ; 28(9): 740-746, 2021 09.
Article in English | MEDLINE | ID: covidwho-1354110
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ABSTRACT
Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, ß-D-N4-hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp-RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / Mutagenesis / Cytidine / SARS-CoV-2 / COVID-19 / Hydroxylamines Limits: Animals / Humans Language: English Journal: Nat Struct Mol Biol Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: S41594-021-00651-0

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Full text: Available Collection: International databases Database: MEDLINE Main subject: RNA, Viral / Mutagenesis / Cytidine / SARS-CoV-2 / COVID-19 / Hydroxylamines Limits: Animals / Humans Language: English Journal: Nat Struct Mol Biol Journal subject: Molecular Biology Year: 2021 Document Type: Article Affiliation country: S41594-021-00651-0