2. Academic Validation
  3. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

  • Nat Struct Mol Biol. 2021 Sep;28(9):740-746. doi: 10.1038/s41594-021-00651-0.
Florian Kabinger # 1,  Carina Stiller # 2,  Jana Schmitzová # 1,  Christian Dienemann 1,  Goran Kokic 1,  Hauke S Hillen 3 4,  Claudia Höbartner 5,  Patrick Cramer 6
Affiliations

Affiliations

  • 1 Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany.
  • 2 Universität Würzburg, Lehrstuhl für Organische Chemie I, Würzburg, Germany.
  • 3 University Medical Center Göttingen, Department of Cellular Biochemistry, Göttingen, Germany.
  • 4 Max Planck Institute for Biophysical Chemistry, Research Group Structure and Function of Molecular Machines, Göttingen, Germany.
  • 5 Universität Würzburg, Lehrstuhl für Organische Chemie I, Würzburg, Germany. claudia.hoebartner@uni-wuerzburg.de.
  • 6 Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany. patrick.cramer@mpibpc.mpg.de.
  • # Contributed equally.
PMID: 34381216 DOI: 10.1038/s41594-021-00651-0
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, β-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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