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X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.
Günther, Sebastian; Reinke, Patrick Y A; Fernández-García, Yaiza; Lieske, Julia; Lane, Thomas J; Ginn, Helen M; Koua, Faisal H M; Ehrt, Christiane; Ewert, Wiebke; Oberthuer, Dominik; Yefanov, Oleksandr; Meier, Susanne; Lorenzen, Kristina; Krichel, Boris; Kopicki, Janine-Denise; Gelisio, Luca; Brehm, Wolfgang; Dunkel, Ilona; Seychell, Brandon; Gieseler, Henry; Norton-Baker, Brenna; Escudero-Pérez, Beatriz; Domaracky, Martin; Saouane, Sofiane; Tolstikova, Alexandra; White, Thomas A; Hänle, Anna; Groessler, Michael; Fleckenstein, Holger; Trost, Fabian; Galchenkova, Marina; Gevorkov, Yaroslav; Li, Chufeng; Awel, Salah; Peck, Ariana; Barthelmess, Miriam; Schlünzen, Frank; Lourdu Xavier, P; Werner, Nadine; Andaleeb, Hina; Ullah, Najeeb; Falke, Sven; Srinivasan, Vasundara; França, Bruno Alves; Schwinzer, Martin; Brognaro, Hévila; Rogers, Cromarte; Melo, Diogo; Zaitseva-Doyle, Joanna J; Knoska, Juraj.
  • Günther S; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany. sebastian.guenther@desy.de alke.meents@desy.de.
  • Reinke PYA; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Fernández-García Y; Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.
  • Lieske J; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Lane TJ; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Ginn HM; Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.
  • Koua FHM; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Ehrt C; Universität Hamburg, Center for Bioinformatics, Bundesstr. 43, 20146 Hamburg, Germany.
  • Ewert W; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Oberthuer D; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Yefanov O; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Meier S; Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • Lorenzen K; Universität Hamburg, Institut für Nanostruktur- und Festkörperphysik, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • Krichel B; European XFEL GmbH, Holzkoppel 4, 22869 Schenefeld, Germany.
  • Kopicki JD; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistr. 52, 20251 Hamburg, Germany.
  • Gelisio L; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistr. 52, 20251 Hamburg, Germany.
  • Brehm W; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Dunkel I; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Seychell B; Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.
  • Gieseler H; Universität Hamburg, Department of Chemistry, Institute of Physical Chemistry, Grindelallee 117, 20146 Hamburg, Germany.
  • Norton-Baker B; Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • Escudero-Pérez B; Universität Hamburg, Institut für Nanostruktur- und Festkörperphysik, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • Domaracky M; Max Planck Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • Saouane S; Department of Chemistry, UC Irvine, Irvine, CA 92697-2025, USA.
  • Tolstikova A; Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.
  • White TA; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Hänle A; Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607, Hamburg, Germany.
  • Groessler M; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Fleckenstein H; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Trost F; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Galchenkova M; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Gevorkov Y; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Li C; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Awel S; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Peck A; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Barthelmess M; Vision Systems, Hamburg University of Technology, 21071 Hamburg, Germany.
  • Schlünzen F; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Lourdu Xavier P; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Werner N; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
  • Andaleeb H; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Ullah N; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Falke S; Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.
  • Srinivasan V; Max Planck Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761 Hamburg, Germany.
  • França BA; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
  • Schwinzer M; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
  • Brognaro H; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
  • Rogers C; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
  • Melo D; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
  • Zaitseva-Doyle JJ; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
  • Knoska J; Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology and Laboratory for Structural Biology of Infection and Inflammation, c/o DESY, 22607 Hamburg, Germany.
Science ; 372(6542): 642-646, 2021 05 07.
Article in English | MEDLINE | ID: covidwho-1166347
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 nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Catalytic Domain / Allosteric Site / Drug Development / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic study Topics: Traditional medicine Limits: Animals Language: English Journal: Science Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Catalytic Domain / Allosteric Site / Drug Development / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic study Topics: Traditional medicine Limits: Animals Language: English Journal: Science Year: 2021 Document Type: Article