SNAP annotations: PDB entry 7ozu

PDB-id

7ozu; DSSR-derived features in text and JSON formats; DNAproDB

Class

viral protein

Method

cryo-EM (3.3 Å)

Summary

Sars-cov-2 rdrp with molnupiravir- nhc in the template strand base-paired with a

Reference

Kabinger F, Stiller C, Schmitzova J, Dienemann C, Kokic G, Hillen HS, Hobartner C, Cramer P (2021): "Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis." Nat.Struct.Mol.Biol., 28, 740-746. 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.