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Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

View ORCID ProfileSebastian Günther, View ORCID ProfilePatrick Y. A. Reinke, Dominik Oberthuer, Oleksandr Yefanov, Helen Ginn, Susanne Meier, Thomas J. Lane, Kristina Lorenzen, Luca Gelisio, Wolfgang Brehm, Illona Dunkel, Martin Domaracky, Sofiane Saouane, Julia Lieske, Christiane Ehrt, Faisal Koua, Alexandra Tolstikova, View ORCID ProfileThomas A. White, Michael Groessler, Holger Fleckenstein, Fabian Trost, Marina Galchenkova, Yaroslav Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, P. Lourdu Xavier, Miriam Barthelmess, Frank Schlünzen, Nadine Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Bruno Alves Franca, Martin Schwinzer, Hévila Brognaro, Brandon Seychell, Henry Gieseler, Diogo Melo, Jo J. Zaitsev-Doyle, Brenna Norton-Baker, Juraj Knoska, Gisel Esperanza, Aida Rahmani Mashhour, Filip Guicking, Vincent Hennicke, Pontus Fischer, Cromarte Rogers, Diana C. F. Monteiro, Johanna Hakanpää, Jan Meyer, Heshmat Noei, Phil Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Linlin Zhang, Xinyuanyuan Sun, Jonathan Pletzer-Zelgert, Jan Wollenhaupt, Christian Feiler, Manfred Weiss, Eike-Christian Schulz, Pedram Mehrabi, Christina Schmidt, Robin Schubert, Huijong Han, Boris Krichel, Yaiza Fernández-García, Beatriz Escudero-Pérez, Stephan Günther, Dusan Turk, Charlotte Uetrecht, Tobias Beck, Henning Tidow, Ashwin Chari, Andrea Zaliani, Matthias Rarey, Russell Cox, Rolf Hilgenfeld, Henry N. Chapman, Arwen R. Pearson, Christian Betzel, Alke Meents
doi: https://doi.org/10.1101/2020.05.02.043554
Sebastian Günther
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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  • ORCID record for Sebastian Günther
  • For correspondence: sebastian.guenther@desy.de alke.meents@desy.de
Patrick Y. A. Reinke
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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  • ORCID record for Patrick Y. A. Reinke
Dominik Oberthuer
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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Oleksandr Yefanov
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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Helen Ginn
2Diamond Light Source Ltd. Diamond House, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK
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Susanne Meier
3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
4Universität Hamburg, Institut für Nanostruktur- und Festkörperphysik, Luruper Chaussee 149, 22761 Hamburg, Germany
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Thomas J. Lane
5Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, California, USA
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Kristina Lorenzen
6European XFEL GmbH. Holzkoppel 4, 22869 Schenefeld, Germany
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Luca Gelisio
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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7Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
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Martin Domaracky
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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Sofiane Saouane
8Deutsches Elektronen Synchrotron (DESY), Photon Science, Notkestrasse 85, 22607, Hamburg, Germany
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Julia Lieske
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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Christiane Ehrt
9Universität Hamburg, Center for Bioinformatics, Bundesstr. 43, 20146 Hamburg, Germany
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Faisal Koua
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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10Vision Systems, Hamburg University of Technology, 21071 Hamburg, Germany
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11Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
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1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
12Max Planck Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761 Hamburg, Germany
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13Universität 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
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3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
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3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
4Universität Hamburg, Institut für Nanostruktur- und Festkörperphysik, Luruper Chaussee 149, 22761 Hamburg, Germany
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Linlin Zhang
17Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
18German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany
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17Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
18German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany
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19Helmholtz Zentrum Berlin, Hahn-Meitner-Platz 1, 14109 Berlin, Germany
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12Max Planck Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761 Hamburg, Germany
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12Max Planck Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761 Hamburg, Germany
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6European XFEL GmbH. Holzkoppel 4, 22869 Schenefeld, Germany
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6European XFEL GmbH. Holzkoppel 4, 22869 Schenefeld, Germany
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Boris Krichel
20Dynamics of Viral Structures, Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Martinistraße 52, 20251 Hamburg, Germany
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Yaiza Fernández-García
21Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Straße 74, 20359 Hamburg, Germany
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Beatriz Escudero-Pérez
21Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Straße 74, 20359 Hamburg, Germany
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21Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Straße 74, 20359 Hamburg, Germany
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Dusan Turk
22Department of Biochemistry & Molecular & Structural Biology, Jozef Stefan Institute, Jamova 39, 1 000 Ljubljana, Slovenia
23Centre of excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKEBIP), Jamova 39, 1 000 Ljubljana,Slovenia
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20Dynamics of Viral Structures, Heinrich-Pette-Institut, Leibniz-Institut für Experimentelle Virologie, Martinistraße 52, 20251 Hamburg, Germany
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Tobias Beck
3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
14Universität Hamburg, Department of Chemistry, Institute of Physical Chemistry, Grindelallee 117, 20146 Hamburg, Germany
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Henning Tidow
3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
24Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
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Ashwin Chari
25Department of Structural Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
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Andrea Zaliani
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9Universität Hamburg, Center for Bioinformatics, Bundesstr. 43, 20146 Hamburg, Germany
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26Institute for Organic Chemistry and BMWZ, Leibniz University of Hannover, Schneiderberg 38, 30167 Hannover, Germany
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Rolf Hilgenfeld
18German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany
27Laboratory for Antiviral Chemotherapy, Institute of Chemistry & Metabolomics and Institute of Molecular Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
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Henry N. Chapman
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
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Arwen R. Pearson
3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
4Universität Hamburg, Institut für Nanostruktur- und Festkörperphysik, Luruper Chaussee 149, 22761 Hamburg, Germany
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Christian Betzel
3Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany
13Universität 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
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Alke Meents
1Center for Free-Electron Laser Science, DESY, Notkestrasse 85, 22607 Hamburg, Germany
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  • For correspondence: sebastian.guenther@desy.de alke.meents@desy.de
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Abstract

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.rcsb.org/structure/6YNQ

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
Sebastian Günther, Patrick Y. A. Reinke, Dominik Oberthuer, Oleksandr Yefanov, Helen Ginn, Susanne Meier, Thomas J. Lane, Kristina Lorenzen, Luca Gelisio, Wolfgang Brehm, Illona Dunkel, Martin Domaracky, Sofiane Saouane, Julia Lieske, Christiane Ehrt, Faisal Koua, Alexandra Tolstikova, Thomas A. White, Michael Groessler, Holger Fleckenstein, Fabian Trost, Marina Galchenkova, Yaroslav Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, P. Lourdu Xavier, Miriam Barthelmess, Frank Schlünzen, Nadine Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Bruno Alves Franca, Martin Schwinzer, Hévila Brognaro, Brandon Seychell, Henry Gieseler, Diogo Melo, Jo J. Zaitsev-Doyle, Brenna Norton-Baker, Juraj Knoska, Gisel Esperanza, Aida Rahmani Mashhour, Filip Guicking, Vincent Hennicke, Pontus Fischer, Cromarte Rogers, Diana C. F. Monteiro, Johanna Hakanpää, Jan Meyer, Heshmat Noei, Phil Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Linlin Zhang, Xinyuanyuan Sun, Jonathan Pletzer-Zelgert, Jan Wollenhaupt, Christian Feiler, Manfred Weiss, Eike-Christian Schulz, Pedram Mehrabi, Christina Schmidt, Robin Schubert, Huijong Han, Boris Krichel, Yaiza Fernández-García, Beatriz Escudero-Pérez, Stephan Günther, Dusan Turk, Charlotte Uetrecht, Tobias Beck, Henning Tidow, Ashwin Chari, Andrea Zaliani, Matthias Rarey, Russell Cox, Rolf Hilgenfeld, Henry N. Chapman, Arwen R. Pearson, Christian Betzel, Alke Meents
bioRxiv 2020.05.02.043554; doi: https://doi.org/10.1101/2020.05.02.043554
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Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
Sebastian Günther, Patrick Y. A. Reinke, Dominik Oberthuer, Oleksandr Yefanov, Helen Ginn, Susanne Meier, Thomas J. Lane, Kristina Lorenzen, Luca Gelisio, Wolfgang Brehm, Illona Dunkel, Martin Domaracky, Sofiane Saouane, Julia Lieske, Christiane Ehrt, Faisal Koua, Alexandra Tolstikova, Thomas A. White, Michael Groessler, Holger Fleckenstein, Fabian Trost, Marina Galchenkova, Yaroslav Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, P. Lourdu Xavier, Miriam Barthelmess, Frank Schlünzen, Nadine Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Bruno Alves Franca, Martin Schwinzer, Hévila Brognaro, Brandon Seychell, Henry Gieseler, Diogo Melo, Jo J. Zaitsev-Doyle, Brenna Norton-Baker, Juraj Knoska, Gisel Esperanza, Aida Rahmani Mashhour, Filip Guicking, Vincent Hennicke, Pontus Fischer, Cromarte Rogers, Diana C. F. Monteiro, Johanna Hakanpää, Jan Meyer, Heshmat Noei, Phil Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Linlin Zhang, Xinyuanyuan Sun, Jonathan Pletzer-Zelgert, Jan Wollenhaupt, Christian Feiler, Manfred Weiss, Eike-Christian Schulz, Pedram Mehrabi, Christina Schmidt, Robin Schubert, Huijong Han, Boris Krichel, Yaiza Fernández-García, Beatriz Escudero-Pérez, Stephan Günther, Dusan Turk, Charlotte Uetrecht, Tobias Beck, Henning Tidow, Ashwin Chari, Andrea Zaliani, Matthias Rarey, Russell Cox, Rolf Hilgenfeld, Henry N. Chapman, Arwen R. Pearson, Christian Betzel, Alke Meents
bioRxiv 2020.05.02.043554; doi: https://doi.org/10.1101/2020.05.02.043554

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