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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.show moreshow less

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Author: Goran KokicORCiD, Hauke S. HillenORCiD, Dimitry TegunovORCiD, Christian Dienermann, Florian Seitz, Jana Schmitzova, Lucas Farnung, Aaron Siewert, Claudia HöbartnerORCiD, Patrick CramerORCiD
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):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International