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TitleMechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Journal, issue, pagesNat Struct Mol Biol, Vol. 28, Issue 9, Page 740-746, Year 2021
Publish dateAug 11, 2021
AuthorsFlorian Kabinger / Carina Stiller / Jana Schmitzová / Christian Dienemann / Goran Kokic / Hauke S Hillen / Claudia Höbartner / Patrick Cramer /
PubMed AbstractMolnupiravir 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 ...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-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.
External linksNat Struct Mol Biol / PubMed:34381216 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 3.3 Å
Structure data

13135

7ozu

EMDB-13135, PDB-7ozu:
SARS-CoV-2 RdRp with Molnupiravir/ NHC in the template strand base-paired with A
Method: EM (single particle) / Resolution: 3.3 Å

13138

7ozv

EMDB-13138, PDB-7ozv:
SARS-CoV-2 RdRp with Molnupiravir/ NHC in the template strand base-paired with G
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
KeywordsVIRAL PROTEIN / SARS-CoV-2 / RNA-dependent RNA polymerase / Molnupiravir (NHC)

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