Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Goran Kokic, Hauke S. Hillen, Dimitry Tegunov, Christian Dienemann, Florian Seitz, Jana Schmitzova, Lucas Farnung, Aaron Siewert, Claudia Höbartner () and Patrick Cramer ()
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Goran Kokic: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology
Hauke S. Hillen: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology
Dimitry Tegunov: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology
Christian Dienemann: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology
Florian Seitz: Universität Würzburg
Jana Schmitzova: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology
Lucas Farnung: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology
Aaron Siewert: Universität Würzburg
Claudia Höbartner: Universität Würzburg
Patrick Cramer: Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology

Nature Communications, 2021, vol. 12, issue 1, 1-7

Abstract: Abstract 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 cryo-electron 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.

Date: 2021
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DOI: 10.1038/s41467-020-20542-0

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