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

authored by: 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.
Organisation(s): Institute of Organic Chemistry
External Organisation(s): Deutsches Elektronen-Synchrotron (DESY)
Bernhard Nocht Institute for Tropical Medicine (BNITM)
Diamond Light Source
Universität Hamburg
European X-Ray Free-Electron Laser Facility GmbH (XFEL)
Heinrich Pette Institute - Leibniz Institute for Experimental Virology (HPI)
Max-Planck Institute for Molecular Genetics (MPIMG)
Max Planck Institute for the Structure and Dynamics of Matter
University of California at Irvine
Hamburg University of Technology (TUHH)
California Institute of Caltech (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 (HZB)
Jožef Stefan Institute (JSI)
Max Planck Institute of Biophysics
University of Greifswald
Type: Article
Journal: SCIENCE
Volume: 372
Pages: 642-646
No. of pages: 5
ISSN: 0036-8075
Publication date: 07.05.2021
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: General
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1126/science.abf7945 (Access: Open)

BibTeX

@article{92949e78f0684b4ab26e5457643fb91e,
title = "X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease",
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.",
author = "Sebastian G{\"u}nther and Reinke, {Patrick Y. A.} and Yaiza Fernandez-Garcia and Julia Lieske and Lane, {Thomas J.} and Ginn, {Helen M.} and Koua, {Faisal H. M.} and Christiane Ehrt and Wiebke Ewert and Dominik Oberthuer and Oleksandr Yefanov and Susanne Meier and Kristina Lorenzen and Boris Krichel and Janine-Denise Kopicki and Luca Gelisio and Wolfgang Brehm and Ilona Dunkel and Brandon Seychell and Henry Gieseler and Brenna Norton-Baker and Beatriz Escudero-Perez and Martin Domaracky and Sofiane Saouane and Alexandra Tolstikova and White, {Thomas A.} and Anna H{\"a}nle and Michael Groessler and Holger Fleckenstein and Fabian Trost and Marina Galchenkova and Yaroslav Gevorkov and Chufeng Li and Salah Awel and Ariana Peck and Miriam Barthelmess and Frank Schl{\"u}nzen and Xavier, {P. Lourdu} and Nadine Werner and Hina Andaleeb and Najeeb Ullah and Sven Falke and Vasundara Srinivasan and Franca, {Bruno Alves} and Martin Schwinzer and Hevila Brognaro and Cromarte Rogers and Diogo Melo and Zaitseva-Doyle, {Joanna J.} and Juraj Knoska and Pena-Murillo, {Gisel E.} and Mashhour, {Aida Rahmani} and Vincent Hennicke and Pontus Fischer and Johanna Hakanp{\"a}{\"a} and Philip Gribbon and Bernhard Ellinger and Maria Kuzikov and Markus Wolf and Beccari, {Andrea R.} and Gleb Bourenkov and {von Stetten}, David and Guillaume Pompidor and Isabel Bento and Saravanan Panneerselvam and Ivars Karpics and Schneider, {Thomas R.} and Garcia-Alai, {Maria Marta} and Stephan Niebling and Christian G{\"u}nther and Christina Schmidt and Robin Schubert and Huijong Han and Juliane Boger and Monteiro, {Diana C. F.} and Linlin Zhang and Xinyuanyuan Sun and Jonathan Pletzer-Zelgert and Jan Wollenhaupt and Feiler, {Christian G.} and Weiss, {Manfred S.} and Eike-Christian Schulz and Pedram Mehrabi and Katarina Karnicar and Aleksandra Usenik and Jure Loboda and Henning Tidow and Ashwin Chari and Rolf Hilgenfeld and Charlotte Uetrecht and Russell Cox and Andrea Zaliani and Tobias Beck and Matthias Rarey and Stephan G{\"u}nther and Dusan Turk and Winfried Hinrichs and Chapman, {Henry N.} and Pearson, {Arwen R.} and Christian Betzel and Alke Meents and Jan Meyer",
year = "2021",
month = may,
day = "7",
doi = "10.1126/science.abf7945",
language = "English",
volume = "372",
pages = "642--646",
journal = "SCIENCE",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6542",
}