X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Sebastian Günther, Sebastian Günther, P. Reinke, Yaiza Fernández-García, J. Lieske, Thomas J. Lane, Helen M. Ginn, F. Koua, Christiane Ehrt, Wiebke Ewert, D. Oberthüer, Oleksandr Yefanov, S. Meier, Kristina Lorenzen, Boris Krichel, Janine-Denise Kopicki, Luca Gelisio, W. Brehm, Ilona Dunkel, B. Seychell, Henry Gieseler, Brenna Norton‐Baker, Beatriz Escudero-Pérez, M. Domaracký, S. Saouane, A. Tolstikova, Thomas A. White, Anna Hänle, M. Groessler, Holger Fleckenstein, F. Trost, M. Galchenkova, Y. Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, Miriam Barthelmeß, Frank Schlünzen, P. Lourdu Xavier, N. Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Vasundara Srinivasan, B. Alves Franca, M. Schwinzer, H. Brognaro, Cromarte Rogers, Diogo Melo, Joanna J. Zaitseva-Doyle, J. Knoška, Gisel E. Peña Murillo, Aida Rahmani Mashhour, V. Hennicke, P. Fischer, Johanna Hakanpää, J. H. Meyer, Philip Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Andrea R. Beccari, Gleb Bourenkov, David von Stetten, Guillaume Pompidor, Isabel Bento, S. Panneerselvam, Ivars Karpičs, T. Schneider, María García-Alai, Stephan Niebling, Christian Günther, Christina Schmidt, Robin Schubert, Huijong Han, J. Boger, Diana C. F. Monteiro, Linlin Zhang, Xinyuanyuan Sun, J. Pletzer-Zelgert, J. Wollenhaupt, C. Feiler, M.S. Weiss, Eike-Christian Schulz, P. Mehrabi, Katarina Karničar, Aleksandra Usenik, Jure Loboda, Henning Tidow, Ashwin Chari, Rolf Hilgenfeld, Charlotte Uetrecht, Russell J. Cox, Andrea Zaliani, Tobias Beck, Matthias Rarey, Stephan Günther, Stephan Günther, Vito Türk, Winfried Hinrichs
Abstract
A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, M pro , is essential to yield functional viral proteins, making it a key drug target. Günther et al. used x-ray crystallography to screen more than 5000 compounds that are either approved drugs or drugs in clinical trials. The screen identified 37 compounds that bind to M pro . High-resolution structures showed that most compounds bind at the active site but also revealed two allosteric sites where binding of a drug causes conformational changes that affect the active site. In cell-based assays, seven compounds had antiviral activity without toxicity. The most potent, calpeptin, binds covalently in the active site, whereas the second most potent, pelitinib, binds at an allosteric site. Science , this issue p. 642