Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
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, ?-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.
Mesh Terms:
Animals, Antiviral Agents, Base Sequence, COVID-19, COVID-19 Drug Treatment, Cytidine, Humans, Hydroxylamines, Models, Molecular, Molecular Structure, Mutagenesis, Mutation, Nucleic Acid Conformation, Protein Binding, Protein Conformation, RNA, Viral, RNA-Dependent RNA Polymerase, SARS-CoV-2, Virus Replication
Animals, Antiviral Agents, Base Sequence, COVID-19, COVID-19 Drug Treatment, Cytidine, Humans, Hydroxylamines, Models, Molecular, Molecular Structure, Mutagenesis, Mutation, Nucleic Acid Conformation, Protein Binding, Protein Conformation, RNA, Viral, RNA-Dependent RNA Polymerase, SARS-CoV-2, Virus Replication
Nat Struct Mol Biol
Date: Sep. 01, 2021
PubMed ID: 34381216
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