Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
2024 | journal article. A publication with affiliation to the University of Göttingen.
Jump to: Cite & Linked | Documents & Media | Details | Version history
Cite this publication
Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
Funk, L.-M.; Poschmann, G.; Rabe von Pappenheim, F.; Chari, A.; Stegmann, K. M.; Dickmanns, A. & Wensien, M. et al. (2024)
Nature Communications, 15(1). DOI: https://doi.org/10.1038/s41467-023-44621-0
Documents & Media
Details
- Authors
- Funk, Lisa-Marie; Poschmann, Gereon; Rabe von Pappenheim, Fabian; Chari, Ashwin; Stegmann, Kim M.; Dickmanns, Antje; Wensien, Marie; Eulig, Nora; Paknia, Elham; Heyne, Gabi; Tittmann, Kai
- 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 (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.
- Issue Date
- 2024
- Journal
- Nature Communications
- eISSN
- 2041-1723
- Language
- English