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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​Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis​
Kabinger, F.; Stiller, C.; Schmitzová, J.; Dienemann, C. ; Kokic, G. ; Hillen, H. S.   & Höbartner, C.  et al.​ (2021) 
Nature Structural & Molecular Biology,.​ DOI: https://doi.org/10.1038/s41594-021-00651-0 

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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) 
ISSN
1545-9993
eISSN
1545-9985
Language
English

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