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Mechanism of SARS-CoV-2 polymerase stalling by remdesivir

Author

Listed:
  • 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
    University Medical Center Göttingen)

  • 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)

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.

Suggested Citation

  • Goran Kokic & Hauke S. Hillen & Dimitry Tegunov & Christian Dienemann & Florian Seitz & Jana Schmitzova & Lucas Farnung & Aaron Siewert & Claudia Höbartner & Patrick Cramer, 2021. "Mechanism of SARS-CoV-2 polymerase stalling by remdesivir," Nature Communications, Nature, vol. 12(1), pages 1-7, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20542-0
    DOI: 10.1038/s41467-020-20542-0
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    Cited by:

    1. Rana Abdelnabi & Caroline S. Foo & Dirk Jochmans & Laura Vangeel & Steven De Jonghe & Patrick Augustijns & Raf Mols & Birgit Weynand & Thanaporn Wattanakul & Richard M. Hoglund & Joel Tarning & Charle, 2022. "The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Shiv Gandhi & Jonathan Klein & Alexander J. Robertson & Mario A. Peña-Hernández & Michelle J. Lin & Pavitra Roychoudhury & Peiwen Lu & John Fournier & David Ferguson & Shah A. K. Mohamed Bakhash & M. , 2022. "De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Leiping Zeng & Yanxia Liu & Xammy Huu Nguyenla & Timothy R. Abbott & Mengting Han & Yanyu Zhu & Augustine Chemparathy & Xueqiu Lin & Xinyi Chen & Haifeng Wang & Draven A. Rane & Jordan M. Spatz & Sake, 2022. "Broad-spectrum CRISPR-mediated inhibition of SARS-CoV-2 variants and endemic coronaviruses in vitro," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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