X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease-Reference-Cited by-同舟云学术

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

Published:2021-05-07 Issue:6542 Volume:372 Page:642-646
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Günther Sebastian¹^ORCID,Reinke Patrick Y. A.¹^ORCID,Fernández-García Yaiza²^ORCID,Lieske Julia¹^ORCID,Lane Thomas J.¹^ORCID,Ginn Helen M.³^ORCID,Koua Faisal H. M.¹^ORCID,Ehrt Christiane⁴^ORCID,Ewert Wiebke¹^ORCID,Oberthuer Dominik¹^ORCID,Yefanov Oleksandr¹,Meier Susanne⁵⁶,Lorenzen Kristina⁷^ORCID,Krichel Boris⁸^ORCID,Kopicki Janine-Denise⁸^ORCID,Gelisio Luca¹^ORCID,Brehm Wolfgang¹^ORCID,Dunkel Ilona⁹,Seychell Brandon¹⁰,Gieseler Henry⁵⁶,Norton-Baker Brenna¹¹¹²^ORCID,Escudero-Pérez Beatriz²,Domaracky Martin¹,Saouane Sofiane¹³^ORCID,Tolstikova Alexandra¹^ORCID,White Thomas A.¹^ORCID,Hänle Anna¹,Groessler Michael¹,Fleckenstein Holger¹^ORCID,Trost Fabian¹^ORCID,Galchenkova Marina¹,Gevorkov Yaroslav¹¹⁴^ORCID,Li Chufeng¹^ORCID,Awel Salah¹^ORCID,Peck Ariana¹⁵^ORCID,Barthelmess Miriam¹,Schlünzen Frank¹^ORCID,Lourdu Xavier P.¹¹¹^ORCID,Werner Nadine¹⁶^ORCID,Andaleeb Hina¹⁶^ORCID,Ullah Najeeb¹⁶^ORCID,Falke Sven¹⁶^ORCID,Srinivasan Vasundara¹⁶^ORCID,França Bruno Alves¹⁶,Schwinzer Martin¹⁶,Brognaro Hévila¹⁶,Rogers Cromarte⁵⁶,Melo Diogo⁵⁶,Zaitseva-Doyle Joanna J.⁵⁶^ORCID,Knoska Juraj¹^ORCID,Peña-Murillo Gisel E.¹^ORCID,Mashhour Aida Rahmani¹,Hennicke Vincent¹^ORCID,Fischer Pontus¹^ORCID,Hakanpää Johanna¹³,Meyer Jan¹³,Gribbon Philip¹⁷,Ellinger Bernhard¹⁷^ORCID,Kuzikov Maria¹⁷^ORCID,Wolf Markus¹⁷,Beccari Andrea R.¹⁸^ORCID,Bourenkov Gleb¹⁹,von Stetten David¹⁹^ORCID,Pompidor Guillaume¹⁹,Bento Isabel¹⁹,Panneerselvam Saravanan¹⁹,Karpics Ivars¹⁹,Schneider Thomas R.¹⁹^ORCID,Garcia-Alai Maria Marta¹⁹,Niebling Stephan¹⁹^ORCID,Günther Christian¹⁹,Schmidt Christina⁷^ORCID,Schubert Robin⁷^ORCID,Han Huijong⁷^ORCID,Boger Juliane²⁰,Monteiro Diana C. F.²¹^ORCID,Zhang Linlin²⁰²²^ORCID,Sun Xinyuanyuan²⁰²²^ORCID,Pletzer-Zelgert Jonathan⁴,Wollenhaupt Jan²³^ORCID,Feiler Christian G.²³^ORCID,Weiss Manfred S.²³^ORCID,Schulz Eike-Christian¹¹^ORCID,Mehrabi Pedram¹¹^ORCID,Karničar Katarina²⁴²⁵^ORCID,Usenik Aleksandra²⁴²⁵^ORCID,Loboda Jure²⁴,Tidow Henning⁵²⁶^ORCID,Chari Ashwin²⁷^ORCID,Hilgenfeld Rolf²⁰²²^ORCID,Uetrecht Charlotte⁸^ORCID,Cox Russell²⁸^ORCID,Zaliani Andrea¹⁷^ORCID,Beck Tobias⁵¹⁰^ORCID,Rarey Matthias⁴^ORCID,Günther Stephan²^ORCID,Turk Dusan²⁴²⁵^ORCID,Hinrichs Winfried¹⁶²⁹^ORCID,Chapman Henry N.¹⁵³⁰^ORCID,Pearson Arwen R.⁵⁶^ORCID,Betzel Christian⁵¹⁶,Meents Alke¹^ORCID

Affiliation:

1. Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607 Hamburg, Germany.

2. Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany.

3. Diamond Light Source Ltd., Diamond House, Harwell Science and Innovation Campus, Didcot, OX11 0DE, UK.

4. Universität Hamburg, Center for Bioinformatics, Bundesstr. 43, 20146 Hamburg, Germany.

5. Hamburg Centre for Ultrafast Imaging, Universität Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.

6. Universität Hamburg, Institut für Nanostruktur- und Festkörperphysik, Luruper Chaussee 149, 22761 Hamburg, Germany.

7. European XFEL GmbH, Holzkoppel 4, 22869 Schenefeld, Germany.

8. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Martinistr. 52, 20251 Hamburg, Germany.

9. Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany.

10. Universität Hamburg, Department of Chemistry, Institute of Physical Chemistry, Grindelallee 117, 20146 Hamburg, Germany.

11. Max Planck Institute for the Structure and Dynamics of Matter, Luruper Chaussee 149, 22761 Hamburg, Germany.

12. Department of Chemistry, UC Irvine, Irvine, CA 92697-2025, USA.

13. Deutsches Elektronen-Synchrotron DESY, Notkestr. 85, 22607, Hamburg, Germany.

14. Vision Systems, Hamburg University of Technology, 21071 Hamburg, Germany.

15. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.

16. 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.

17. Fraunhofer Institute for Translational Medicine and Pharmacology and Fraunhofer Cluster of Excellence for Immune Mediated Diseases, Schnackenburgallee 114, 22525 Hamburg, Germany.

18. Dompé Farmaceutici SpA, 67100 L’Aquila, Italy.

19. EMBL Outstation Hamburg, c/o DESY, Notkestr. 85, 22607 Hamburg, Germany.

20. Institute of Molecular Medicine, University of Lübeck, 23562 Lübeck, Germany.

21. Hauptmann Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, USA.

22. German Center for Infection Research, Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.

23. Helmholtz Zentrum Berlin, Macromolecular Crystallography, Albert-Einstein-Str. 15, 12489 Berlin, Germany.

24. Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.

25. Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova 39, 1000 Ljubljana, Slovenia.

26. Universität Hamburg, Department of Chemistry, Institute of Biochemistry and Molecular Biology, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.

27. Research Group for Structural Biochemistry and Mechanisms, Department of Structural Dynamics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.

28. Institute for Organic Chemistry and BMWZ, Leibniz University of Hannover, Schneiderberg 38, 30167 Hannover, Germany.

29. Universität Greifswald, Institute of Biochemistry, Felix-Hausdorff-Str. 4, 17489 Greifswald, Germany.

30. Universität Hamburg, Department of Physics, Luruper Chaussee 149, 22761 Hamburg, Germany.

Abstract

A large-scale screen to target SARS-CoV-2 The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is initially expressed as two large polyproteins. Its main protease, M pro , is essential to yield functional viral proteins, making it a key drug target. Günther et al. used x-ray crystallography to screen more than 5000 compounds that are either approved drugs or drugs in clinical trials. The screen identified 37 compounds that bind to M pro . High-resolution structures showed that most compounds bind at the active site but also revealed two allosteric sites where binding of a drug causes conformational changes that affect the active site. In cell-based assays, seven compounds had antiviral activity without toxicity. The most potent, calpeptin, binds covalently in the active site, whereas the second most potent, pelitinib, binds at an allosteric site. Science , this issue p. 642

Funder

Slovenian Research Agency

Deutsche Forschungsgemeinschaft

Boehringer Ingelheim Foundation

EXSCALATE4CoV EU-H2020

the Federal Ministry of Education and Research

Joachim-Herz-Stiftung Hamburg

HELMHOLTZ Graduate School for the Structure of Matter

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary