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Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design

Author

Listed:
  • Lisa-Marie Funk

    (Georg-August University Göttingen
    Max-Planck-Institute for Multidisciplinary Sciences)

  • Gereon Poschmann

    (Heinrich-Heine University Düsseldorf)

  • Fabian Rabe von Pappenheim

    (Georg-August University Göttingen
    Max-Planck-Institute for Multidisciplinary Sciences)

  • Ashwin Chari

    (Max-Planck-Institute for Multidisciplinary Sciences)

  • Kim M. Stegmann

    (University Medical Center Göttingen)

  • Antje Dickmanns

    (University Medical Center Göttingen)

  • Marie Wensien

    (Georg-August University Göttingen
    Max-Planck-Institute for Multidisciplinary Sciences)

  • Nora Eulig

    (Georg-August University Göttingen
    Max-Planck-Institute for Multidisciplinary Sciences)

  • Elham Paknia

    (Max-Planck-Institute for Multidisciplinary Sciences)

  • Gabi Heyne

    (Max-Planck-Institute for Multidisciplinary Sciences)

  • Elke Penka

    (Georg-August University Göttingen
    Max-Planck-Institute for Multidisciplinary Sciences)

  • Arwen R. Pearson

    (Hamburg University, HARBOR)

  • Carsten Berndt

    (Heinrich-Heine University Düsseldorf)

  • Tobias Fritz

    (Georg-August University Göttingen)

  • Sophia Bazzi

    (Georg-August University Göttingen)

  • Jon Uranga

    (Georg-August University Göttingen)

  • Ricardo A. Mata

    (Georg-August University Göttingen)

  • Matthias Dobbelstein

    (University Medical Center Göttingen)

  • Rolf Hilgenfeld

    (Lübeck University
    University of Lübeck)

  • Ute Curth

    (Hannover Medical School)

  • Kai Tittmann

    (Georg-August University Göttingen
    Max-Planck-Institute for Multidisciplinary Sciences)

Abstract

Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (Mpro), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that Mpro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit Mpro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44621-0
    DOI: 10.1038/s41467-023-44621-0
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    1. Patrick Y. A. Reinke & Robin Schubert & Dominik Oberthür & Marina Galchenkova & Aida Rahmani Mashhour & Sebastian Günther & Anaïs Chretien & Adam Round & Brandon Charles Seychell & Brenna Norton-Baker, 2024. "SARS-CoV-2 Mpro responds to oxidation by forming disulfide and NOS/SONOS bonds," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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