TY  - JOUR
A1  - Kabinger, Florian
A1  - Stiller, Carina
A1  - Schmitzová, Jana
A1  - Dienemann, Christian
A1  - Kokic, Goran
A1  - Hillen, Hauke S.
A1  - Höbartner, Claudia
A1  - Cramer, Patrick
T1  - Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis
T2  - Nature Structural & Molecular Biology
N2  - 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.
KW  - Molnupiravir
KW  - RNA-Dependent RNA Polymerase
KW  - SARS-CoV2 Replication Impairment
KW  - Molnupiravir-Induced RNA Mutagenesis Mechanism
KW  - Cryoelectron Microscopy
Y1  - 2021
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/25460
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-254603
VL  - 28
ER  -