Science
. 2021 Apr 2;eabf7945.
doi: 10.1126/science.abf7945. Online ahead of print.
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Sebastian G?nther # 1 , Patrick Y A Reinke # 2 , Yaiza Fern?ndez-Garc?a 3 , Julia Lieske 2 , Thomas J Lane 2 , Helen M Ginn 4 , Faisal H M Koua 2 , Christiane Ehrt 5 , Wiebke Ewert 2 , Dominik Oberthuer 2 , Oleksandr Yefanov 2 , Susanne Meier 6 7 , Kristina Lorenzen 8 , Boris Krichel 9 , Janine-Denise Kopicki 9 , Luca Gelisio 2 , Wolfgang Brehm 2 , Ilona Dunkel 10 , Brandon Seychell 11 , Henry Gieseler 6 7 , Brenna Norton-Baker 12 13 , Beatriz Escudero-P?rez 3 , Martin Domaracky 2 , Sofiane Saouane 14 , Alexandra Tolstikova 2 , Thomas A White 2 , Anna H?nle 2 , Michael Groessler 2 , Holger Fleckenstein 2 , Fabian Trost 2 , Marina Galchenkova 2 , Yaroslav Gevorkov 2 15 , Chufeng Li 2 , Salah Awel 2 , Ariana Peck 16 , Miriam Barthelmess 2 , Frank Schluenzen 2 , Paulraj Lourdu Xavier 2 12 , Nadine Werner 17 , Hina Andaleeb 17 , Najeeb Ullah 17 , Sven Falke 17 , Vasundara Srinivasan 17 , Bruno Alves Fran?a 17 , Martin Schwinzer 17 , H?vila Brognaro 17 , Cromarte Rogers 6 7 , Diogo Melo 6 7 , Joanna J Zaitseva-Doyle 6 7 , Juraj Knoska 2 , Gisel E Pe?a-Murillo 2 , Aida Rahmani Mashhour 2 , Vincent Hennicke 2 , Pontus Fischer 2 , Johanna Hakanp?? 14 , Jan Meyer 14 , Philip Gribbon 18 , Bernhard Ellinger 18 , Maria Kuzikov 18 , Markus Wolf 18 , Andrea R Beccari 19 , Gleb Bourenkov 20 , David von Stetten 20 , Guillaume Pompidor 20 , Isabel Bento 20 , Saravanan Panneerselvam 20 , Ivars Karpics 20 , Thomas R Schneider 20 , Maria Marta Garcia-Alai 20 , Stephan Niebling 20 , Christian G?nther 20 , Christina Schmidt 8 , Robin Schubert 8 , Huijong Han 8 , Juliane Boger 21 , Diana C F Monteiro 22 , Linlin Zhang 21 23 , Xinyuanyuan Sun 21 23 , Jonathan Pletzer-Zelgert 5 , Jan Wollenhaupt 24 , Christian G Feiler 24 , Manfred S Weiss 24 , Eike-Christian Schulz 12 , Pedram Mehrabi 12 , Katarina Karni?ar 25 26 , Aleksandra Usenik 25 26 , Jure Loboda 25 , Henning Tidow 6 27 , Ashwin Chari 28 , Rolf Hilgenfeld 21 23 , Charlotte Uetrecht 9 , Russell Cox 29 , Andrea Zaliani 18 , Tobias Beck 6 11 , Matthias Rarey 5 , Stephan G?nther 3 , Dusan Turk 25 26 , Winfried Hinrichs 17 30 , Henry N Chapman 2 6 31 , Arwen R Pearson 6 7 , Christian Betzel 6 17 , Alke Meents 1
Affiliations
- PMID: 33811162
- DOI: 10.1126/science.abf7945
Abstract
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 already approved 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 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.