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Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Author

Listed:
  • Alice Douangamath

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • Daren Fearon

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus)

  • Paul Gehrtz

    (Weizmann Institute of Science)

  • Tobias Krojer

    (Structural Genomics Consortium, University of Oxford)

  • Petra Lukacik

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • C. David Owen

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • Efrat Resnick

    (Weizmann Institute of Science)

  • Claire Strain-Damerell

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • Anthony Aimon

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • Péter Ábrányi-Balogh

    (Medicinal Chemistry Research Group, Research Centre for Natural Sciences)

  • José Brandão-Neto

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • Anna Carbery

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    University of Oxford)

  • Gemma Davison

    (Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University)

  • Alexandre Dias

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus)

  • Thomas D. Downes

    (University of York)

  • Louise Dunnett

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus)

  • Michael Fairhead

    (Structural Genomics Consortium, University of Oxford)

  • James D. Firth

    (University of York)

  • S. Paul Jones

    (University of York)

  • Aaron Keeley

    (Medicinal Chemistry Research Group, Research Centre for Natural Sciences)

  • György M. Keserü

    (Medicinal Chemistry Research Group, Research Centre for Natural Sciences)

  • Hanna F. Klein

    (University of York)

  • Mathew P. Martin

    (Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle University)

  • Martin E. M. Noble

    (Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle University)

  • Peter O’Brien

    (University of York)

  • Ailsa Powell

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus)

  • Rambabu N. Reddi

    (Weizmann Institute of Science)

  • Rachael Skyner

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

  • Matthew Snee

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus)

  • Michael J. Waring

    (Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University)

  • Conor Wild

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus)

  • Nir London

    (Weizmann Institute of Science)

  • Frank Delft

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus
    Structural Genomics Consortium, University of Oxford
    University of Johannesburg)

  • Martin A. Walsh

    (Diamond Light Source Ltd., Harwell Science and Innovation Campus
    Research Complex at Harwell, Harwell Science and Innovation Campus)

Abstract

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

Suggested Citation

  • Alice Douangamath & Daren Fearon & Paul Gehrtz & Tobias Krojer & Petra Lukacik & C. David Owen & Efrat Resnick & Claire Strain-Damerell & Anthony Aimon & Péter Ábrányi-Balogh & José Brandão-Neto & Ann, 2020. "Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18709-w
    DOI: 10.1038/s41467-020-18709-w
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    Cited by:

    1. Jaeyong Lee & Calem Kenward & Liam J. Worrall & Marija Vuckovic & Francesco Gentile & Anh-Tien Ton & Myles Ng & Artem Cherkasov & Natalie C. J. Strynadka & Mark Paetzel, 2022. "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Lisa-Marie Funk & Gereon Poschmann & Fabian Rabe von Pappenheim & Ashwin Chari & Kim M. Stegmann & Antje Dickmanns & Marie Wensien & Nora Eulig & Elham Paknia & Gabi Heyne & Elke Penka & Arwen R. Pear, 2024. "Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Ronen Gabizon & Barr Tivon & Rambabu N. Reddi & Maxime C. M. Oetelaar & Hadar Amartely & Peter J. Cossar & Christian Ottmann & Nir London, 2023. "A simple method for developing lysine targeted covalent protein reagents," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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