Inhibition of SARS-CoV-2 main protease by allosteric drug-binding

Günther, Sebastian; Reinke, Patrick Y. A.; Fernández-García, Yaiza; Lieske, Julia; Lane, Thomas J.; Ginn, Helen M.; Koua, Faisal H. M.; Ehrt, Christiane; Ewert, Wiebke; Oberthuer, Dominik; Yefanov, Oleksandr; Meier, Susanne; Lorenzen, Kristina; Krichel, Boris; Kopicki, Janine-Denise; Gelisio, Luca; Brehm, Wolfgang; Dunkel, Ilona; Seychell, Brandon; Gieseler, Henry; Norton-Baker, Brenna; Escudero-Pérez, Beatriz; Domaracky, Martin; Saouane, Sofiane; Tolstikova, Alexandra; White, Thomas A.; Hänle, Anna; Groessler, Michael; Fleckenstein, Holger; Trost, Fabian; Galchenkova, Marina; Gevorkov, Yaroslav; Li, Chufeng; Awel, Salah; Peck, Ariana; Barthelmess, Miriam; Schlünzen, Frank; Xavier, P. Lourdu; Werner, Nadine; Andaleeb, Hina; Ullah, Najeeb; Falke, Sven; Srinivasan, Vasundara; Franca, Bruno Alves; Schwinzer, Martin; Brognaro, Hévila; Rogers, Cromarte; Melo, Diogo; Zaitsev-Doyle, Jo J.; Knoska, Juraj; Peña Murillo, Gisel E.; Mashhour, Aida Rahmani; Guicking, Filip; Hennicke, Vincent; Fischer, Pontus; Hakanpää, Johanna; Meyer, Jan; Gribbon, Phil; Ellinger, Bernhard; Kuzikov, Maria; Wolf, Markus; Beccari, Andrea R.; Bourenkov, Gleb; Stetten, David von; Pompidor, Guillaume; Bento, Isabel; Panneerselvam, Saravanan; Karpics, Ivars; Schneider, Thomas R.; Garcia Alai, Maria Marta; Niebling, Stephan; Günther, Christian; Schmidt, Christina; Schubert, Robin; Han, Huijong; Boger, Juliane; Monteiro, Diana C. F.; Zhang, Linlin; Sun, Xinyuanyuan; Pletzer-Zelgert, Jonathan; Wollenhaupt, Jan; Feiler, Christian G.; Weiss, Manfred S.; Schulz, Eike-Christian; Mehrabi, Pedram; Karničar, Katarina; Usenik, Aleksandra; Loboda, Jure; Tidow, Henning; Chari, Ashwin; Hilgenfeld, Rolf; Uetrecht, Charlotte; Cox, Russell; Zaliani, Andrea; Beck, Tobias; Rarey, Matthias; Günther, Stephan; Turk, Dusan; Hinrichs, Winfried; Chapman, Henry N.; Pearson, Arwen R.; Betzel, Christian; Meents, Alke

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.