Journal Article

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

Rabe von Pappenheim, Fabian, Tittmann, Kai, Chari, Ashwin, Uranga, Jon, Penka, Elke, Dobbelstein, Matthias, Funk, Lisa-Marie, Pearson, Arwen R., Eulig, Nora, Mata, Ricardo A., Berndt, Carsten, Curth, Ute, Fritz, Tobias, Bazzi, Sophia, Paknia, Elham, Wensien, Marie, Heyne, Gabi, Stegmann, Kim M., Poschmann, Gereon, Dickmanns, Antje, Hilgenfeld, Rolf

2024

Overview

Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (M pro ), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M pro 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 M pro 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. Here the authors demonstrate that the SARS-CoV-2 main protease (Mpro) is subject to redox regulation in vitro, reversibly switching between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/45/173 / 631/45/2783 / 631/45/535/1266 / 631/45/607/468 / 82/1 / 82/58 / 82/80 / 82/83 / Allosteric properties / Antiviral agents / Antiviral drugs / Coronavirus 3C Proteases / Coronaviruses / COVID-19 / Cysteine / Cysteine proteinase / Dimers / Drug delivery / Drug Design / Drug development / Humanities and Social Sciences / Humans / Immune system / Immunosuppressive agents / Innate immunity / Lysine / Monomers / multidisciplinary / Oxidation-Reduction / Oxidative stress / Protease / Reagents / Residues / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Structural stability / Switches / Switching / Therapeutic targets / Viral diseases