Redox regulation of the SARS-CoV-2 main protease provides new opportunities for drug design

Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future outbreaks. The SARS-CoV-2 main protease (Mpro), a cysteine protease with essential functions in viral replication, has been validated as an effective...

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Published in:bioRxiv 2022-04
Main Authors: Tittmann, Kai, Funk, Lisa-Marie, Poschmann, Gereon, Chari, Ashwin, Fabian Rabe Von Pappenheim, Stegmann, Kim Maren, Dickmanns, Antje, Eulig, Nora, Wensien, Marie, Paknia, Elham, Heyne, Gabi, Penka, Elke, Pearson, Arwen R, Berndt, Carsten, Fritz, Tobias, Bazzi, Sophia, Uranga, Jon, Mata, Ricardo A, Dobbelstein, Matthias, Hilgenfeld, Rolf, Curth, Ute
Format: Article
Language:English
Subjects:
Allosteric properties
Antiviral activity
Antiviral agents
Coronaviruses
COVID-19
Cysteine
Cysteine proteinase
Drug delivery
Drug development
Immune system
Immunosuppressive agents
Innate immunity
Lysine
Oxidative stress
Severe acute respiratory syndrome coronavirus 2
Therapeutic targets
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Summary:Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for stopping the current COVID-19 pandemic and preventing future 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 and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include sulfenylation, disulfide formation between the catalytic cysteine and a proximal cysteine, and generation of an allosteric 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 possess antiviral activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS and SARS-CoV, indicating their potential as common druggable sites. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2022.04.18.487732