@article{KabingerStillerSchmitzovaetal.2021,
  author    = {Kabinger, Florian and Stiller, Carina and Schmitzov{\´a}, Jana and Dienemann, Christian and Kokic, Goran and Hillen, Hauke S. and H{\"o}bartner, Claudia and Cramer, Patrick},
  title     = {Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis},
  series = {Nature Structural \& Molecular Biology},
  volume    = {28},
  journal   = {Nature Structural \& Molecular Biology},
  doi       = {10.1038/s41594-021-00651-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254603},
  pages     = {740-746},
  year      = {2021},
  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-\(N^4\)-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.},
  language  = {en}
}