Mechanism of SARS-CoV-2 polymerase stalling by remdesivir
Please always quote using this URN: urn:nbn:de:bvb:20-opus-220979
- Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryoelectron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show thatRemdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryoelectron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.…
Author: | Goran KokicORCiD, Hauke S. HillenORCiD, Dimitry TegunovORCiD, Christian Dienermann, Florian Seitz, Jana Schmitzova, Lucas Farnung, Aaron Siewert, Claudia HöbartnerORCiD, Patrick CramerORCiD |
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URN: | urn:nbn:de:bvb:20-opus-220979 |
Document Type: | Journal article |
Faculties: | Fakultät für Chemie und Pharmazie / Institut für Organische Chemie |
Language: | English |
Parent Title (English): | Nature Communications |
Year of Completion: | 2021 |
Volume: | 12 |
Article Number: | 279 |
Source: | Nature Communications (2021) 12:279. https://doi.org/10.1038/s41467-020-205 |
DOI: | https://doi.org/10.1038/s41467-020-20542-0 |
Sonstige beteiligte Institutionen: | Max-Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen |
Sonstige beteiligte Institutionen: | Department of Cellular Biochemistry, University Medical Center Göttingen |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften |
Tag: | Biochemistry; Cryoelectron microscopy; Molecular mechanism; RNA; RNA-dependent RNA polymerase; Remdesivir; SARS-CoV-2 polymerase |
Release Date: | 2021/01/19 |
EU-Project number / Contract (GA) number: | 693023 |
EU-Project number / Contract (GA) number: | 682586 |
OpenAIRE: | OpenAIRE |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |