English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

Kabinger, F., Stiller, C., Schmitzova, J., Dienemann, C., Kokic, G., Hillen, H. S., et al. (2021). Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nature Structural and Molecular Biology, 28(9), 740-746. doi:10.1038/s41594-021-00651-0.

Item is

Basic

show hide
Genre: Journal Article

Files

show Files
hide Files
:
3337534.pdf (Publisher version), 6MB
Name:
3337534.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
-

Locators

show

Creators

show
hide
 Creators:
Kabinger, F.1, Author              
Stiller, C., Author
Schmitzova, J.1, Author              
Dienemann, C.1, Author              
Kokic, G.1, Author              
Hillen, H. S.2, Author              
Höbartner, C., Author
Cramer, P.1, Author              
Affiliations:
1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              
2Research Group Structure and Function of Molecular Machines, MPI for Biophysical Chemistry, Max Planck Society, ou_3265856              

Content

show
hide
Free keywords: Cryoelectron mircroscopy
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2021-08-112021-09
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41594-021-00651-0
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Nature Structural and Molecular Biology
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 28 (9) Sequence Number: - Start / End Page: 740 - 746 Identifier: -