X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

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

Organisationseinheit(en)
Institut für Organische Chemie
Externe Organisation(en)
Deutsches Elektronen-Synchrotron (DESY)
Bernhard-Nocht-Institut für Tropenmedizin (BNITM)
Diamond Light Source
Universität Hamburg
European X-Ray Free-Electron Laser Facility GmbH (XFEL)
Heinrich-Pette-Institut Leibniz-Institut für Experimentelle Virologie (HPI)
Max-Planck-Institut für molekulare Genetik (MPIMG)
Max-Planck-Institut für Struktur und Dynamik der Materie
University of California at Irvine
Technische Universität Hamburg (TUHH)
California Institute of Technology (Caltech)
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP
Dompé Farmaceutici SpA
Universität zu Lübeck
Hauptman-Woodward Medical Research Institute
Helmholtz-Zentrum Berlin für Materialien und Energie GmbH
Institut "Jožef Stefan" (IJS)
Max-Planck-Institut für Biophysik
Universität Greifswald
Typ
Artikel
Journal
SCIENCE
Band
372
Seiten
642-646
Anzahl der Seiten
5
ISSN
0036-8075
Publikationsdatum
07.05.2021
Publikationsstatus
Veröffentlicht
Peer-reviewed
Ja
ASJC Scopus Sachgebiete
Allgemein
Ziele für nachhaltige Entwicklung
SDG 3 – Gute Gesundheit und Wohlergehen
Elektronische Version(en)
https://doi.org/10.1126/science.abf7945 (Zugang: Offen)