Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis
2021 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Details
- Authors
- Kabinger, Florian; Stiller, Carina; Schmitzová, Jana; Dienemann, C. ; Kokic, Goran ; Hillen, Hauke S. ; Höbartner, Claudia ; Cramer, Patrick
- Abstract
- 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.
- Issue Date
- 2021
- Journal
- Nature Structural & Molecular Biology
- Project
- EXC 2067: Multiscale Bioimaging
SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente
FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala
FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane - Working Group
- RG Cramer
RG Hillen (Structure and Function of Molecular Machines) - External URL
- https://mbexc.uni-goettingen.de/literature/publications/381
https://sfb1190.med.uni-goettingen.de/production/literature/publications/171
https://for2848.gwdguser.de/literature/publications/28 - ISSN
- 1545-9993
- eISSN
- 1545-9985
- Language
- English