tetano
Editor, Senior Moderator
Nat Commun
. 2024 Jan 9;15(1):411.
doi: 10.1038/s41467-023-44621-0. Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
Lisa-Marie Funk[SUP] 1 2 [/SUP], Gereon Poschmann[SUP] 3 [/SUP], Fabian Rabe von Pappenheim[SUP] 1 2 [/SUP], Ashwin Chari[SUP] 4 [/SUP], Kim M Stegmann[SUP] 5 [/SUP], Antje Dickmanns[SUP] 5 [/SUP], Marie Wensien[SUP] 1 2 [/SUP], Nora Eulig[SUP] 1 2 [/SUP], Elham Paknia[SUP] 4 [/SUP], Gabi Heyne[SUP] 4 [/SUP], Elke Penka[SUP] 1 2 [/SUP], Arwen R Pearson[SUP] 6 [/SUP], Carsten Berndt[SUP] 7 [/SUP], Tobias Fritz[SUP] 8 [/SUP], Sophia Bazzi[SUP] 8 [/SUP], Jon Uranga[SUP] 8 [/SUP], Ricardo A Mata[SUP] 8 [/SUP], Matthias Dobbelstein[SUP] 5 [/SUP], Rolf Hilgenfeld[SUP] 9 10 [/SUP], Ute Curth[SUP] 11 [/SUP], Kai Tittmann[SUP] 12 13 [/SUP]
Affiliations
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[SUP]pro[/SUP]), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M[SUP]pro[/SUP] 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[SUP]pro[/SUP] 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.
. 2024 Jan 9;15(1):411.
doi: 10.1038/s41467-023-44621-0. Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
Lisa-Marie Funk[SUP] 1 2 [/SUP], Gereon Poschmann[SUP] 3 [/SUP], Fabian Rabe von Pappenheim[SUP] 1 2 [/SUP], Ashwin Chari[SUP] 4 [/SUP], Kim M Stegmann[SUP] 5 [/SUP], Antje Dickmanns[SUP] 5 [/SUP], Marie Wensien[SUP] 1 2 [/SUP], Nora Eulig[SUP] 1 2 [/SUP], Elham Paknia[SUP] 4 [/SUP], Gabi Heyne[SUP] 4 [/SUP], Elke Penka[SUP] 1 2 [/SUP], Arwen R Pearson[SUP] 6 [/SUP], Carsten Berndt[SUP] 7 [/SUP], Tobias Fritz[SUP] 8 [/SUP], Sophia Bazzi[SUP] 8 [/SUP], Jon Uranga[SUP] 8 [/SUP], Ricardo A Mata[SUP] 8 [/SUP], Matthias Dobbelstein[SUP] 5 [/SUP], Rolf Hilgenfeld[SUP] 9 10 [/SUP], Ute Curth[SUP] 11 [/SUP], Kai Tittmann[SUP] 12 13 [/SUP]
Affiliations
- PMID: 38195625
- PMCID: PMC10776599
- DOI: 10.1038/s41467-023-44621-0
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[SUP]pro[/SUP]), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that M[SUP]pro[/SUP] 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[SUP]pro[/SUP] 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.