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

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. Pearson, Carsten Berndt, Tobias Fritz, Sophia Bazzi, Jon Uranga, Ricardo A. Mata, Matthias Dobbelstein, Rolf Hilgenfeld, Ute Curth and Kai Tittmann ()
Additional contact information
Lisa-Marie Funk: Georg-August University Göttingen
Gereon Poschmann: Heinrich-Heine University Düsseldorf
Fabian Rabe von Pappenheim: Georg-August University Göttingen
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
Nora Eulig: Georg-August University Göttingen
Elham Paknia: Max-Planck-Institute for Multidisciplinary Sciences
Gabi Heyne: Max-Planck-Institute for Multidisciplinary Sciences
Elke Penka: Georg-August University Göttingen
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
Ute Curth: Hannover Medical School
Kai Tittmann: Georg-August University Göttingen

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44621-0

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