Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis

Please always quote using this URN: urn:nbn:de:bvb:20-opus-254603
  • 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 substrateMolnupiravir 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.show moreshow less

Download full text files

Export metadata

Metadaten
Author: Florian KabingerORCiD, Carina StillerORCiD, Jana Schmitzová, Christian Dienemann, Goran KokicORCiD, Hauke S. HillenORCiD, Claudia HöbartnerORCiD, Patrick CramerORCiD
URN:urn:nbn:de:bvb:20-opus-254603
Document Type:Journal article
Faculties:Fakultät für Chemie und Pharmazie / Institut für Organische Chemie
Language:English
Parent Title (English):Nature Structural & Molecular Biology
Year of Completion:2021
Volume:28
Pagenumber:740-746
Source:Nature Structural & Molecular Biology (2021) 28, 740–746. https://doi.org/10.1038/s41594-021-00651-0
DOI:https://doi.org/10.1038/s41594-021-00651-0
Sonstige beteiligte Institutionen:Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen
Sonstige beteiligte Institutionen:University Medical Center Göttingen, Department of Cellular Biochemistry, Göttingen
Sonstige beteiligte Institutionen:Max Planck Institute for Biophysical Chemistry, Research Group Structure and Function of Molecular Machines, Göttingen
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Tag:Cryoelectron Microscopy; Molnupiravir; Molnupiravir-Induced RNA Mutagenesis Mechanism; RNA-Dependent RNA Polymerase; SARS-CoV2 Replication Impairment
Release Date:2022/02/03
EU-Project number / Contract (GA) number:693023
EU-Project number / Contract (GA) number:682586
OpenAIRE:OpenAIRE
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International