X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Creators: name: Günther, Sebastian
name: Reinke, Patrick Y. A.
name: Fernández-García, Yaiza
name: Lieske, Julia
name: Lane, Thomas J.
name: Ginn, Helen M.
name: Koua, Faisal H. M.
name: Ehrt, Christiane
name: Ewert, Wiebke
name: Oberthuer, Dominik
name: Yefanov, Oleksandr
name: Meier, Susanne
name: Lorenzen, Kristina
name: Krichel, Boris
name: Kopicki, Janine-Denise
name: Gelisio, Luca
name: Brehm, Wolfgang
name: Dunkel, Ilona
name: Seychell, Brandon
name: Gieseler, Henry
name: Norton-Baker, Brenna
name: Escudero-Pérez, Beatriz
name: Domaracky, Martin
name: Saouane, Sofiane
name: Tolstikova, Alexandra
name: White, Thomas A.
name: Hänle, Anna
name: Groessler, Michael
name: Fleckenstein, Holger
name: Trost, Fabian
name: Galchenkova, Marina
name: Gevorkov, Yaroslav
name: Li, Chufeng
name: Awel, Salah
name: Peck, Ariana
name: Barthelmess, Miriam
name: Schlünzen, Frank
name: Lourdu Xavier, P.
name: Werner, Nadine
name: Andaleeb, Hina
name: Ullah, Najeeb
name: Falke, Sven
name: Srinivasan, Vasundara
name: França, Bruno Alves
name: Schwinzer, Martin
name: Brognaro, Hévila
name: Rogers, Cromarte
name: Melo, Diogo
name: Zaitseva-Doyle, Joanna J.
name: Knoska, Juraj
name: Peña-Murillo, Gisel E.
name: Mashhour, Aida Rahmani
name: Hennicke, Vincent
name: Fischer, Pontus
name: Hakanpää, Johanna
name: Meyer, Jan
name: Gribbon, Philip
name: Ellinger, Bernhard
name: Kuzikov, Maria
name: Wolf, Markus
name: Beccari, Andrea R.
name: Bourenkov, Gleb
name: Von Stetten, David
name: Pompidor, Guillaume
name: Bento, Isabel
name: Panneerselvam, Saravanan
name: Karpics, Ivars
name: Schneider, Thomas R.
name: Garcia-Alai, Maria Marta
name: Niebling, Stephan
name: Günther, Christian
name: Schmidt, Christina
name: Schubert, Robin
name: Han, Huijong
name: Boger, Juliane
name: Monteiro, Diana C. F.
name: Zhang, Linlin
name: Sun, Xinyuanyuan
name: Pletzer-Zelgert, Jonathan
name: Wollenhaupt, Jan
name: Feiler, Christian G.
name: Weiss, Manfred S.
name: Schulz, Eike-Christian
name: Mehrabi, Pedram
name: Karničar, Katarina
name: Usenik, Aleksandra
name: Loboda, Jure
name: Tidow, Henning
name: Chari, Ashwin
name: Hilgenfeld, Rolf
name: Uetrecht, Charlotte
name: Cox, Russell
name: Zaliani, Andrea
name: Beck, Tobias
name: Rarey, Matthias
name: Günther, Stephan
name: Turk, Dusan
name: Hinrichs, Winfried
name: Chapman, Henry N.
name: Pearson, Arwen R.
name: Betzel, Christian
name: Meents, Alke
Publisher: name: Washington, DC : American Association for the Advancement of Science
Year: 2021
Subjects: subject: Allosteric Site
subject: Animals
subject: Antiviral Agents
subject: Catalytic Domain
subject: Chlorocebus aethiops
subject: Dewey Decimal Classification::500 | Naturwissenschaften

description: The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested alreadyapproved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.