Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis
Zitieren Sie bitte immer diese 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.…
Autor(en): | Florian KabingerORCiD, Carina StillerORCiD, Jana Schmitzová, Christian Dienemann, Goran KokicORCiD, Hauke S. HillenORCiD, Claudia HöbartnerORCiD, Patrick CramerORCiD |
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URN: | urn:nbn:de:bvb:20-opus-254603 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Chemie und Pharmazie / Institut für Organische Chemie |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Nature Structural & Molecular Biology |
Erscheinungsjahr: | 2021 |
Band / Jahrgang: | 28 |
Seitenangabe: | 740-746 |
Originalveröffentlichung / Quelle: | 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 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Freie Schlagwort(e): | Cryoelectron Microscopy; Molnupiravir; Molnupiravir-Induced RNA Mutagenesis Mechanism; RNA-Dependent RNA Polymerase; SARS-CoV2 Replication Impairment |
Datum der Freischaltung: | 03.02.2022 |
EU-Projektnummer / Contract (GA) number: | 693023 |
EU-Projektnummer / Contract (GA) number: | 682586 |
OpenAIRE: | OpenAIRE |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |