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
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
Ernst-Moritz-Arndt-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)

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",
}