Open Access

Science

, volume 372 , issue 6542 , pages 642-646

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

Sebastian Günther ¹

Patrick Reinke ¹

Yaiza Fernández García ²

Julia Lieske ¹

T.M. Lane ¹

Helen Mary Ginn ³

Faisal H. M. Koua ¹

Christiane Ehrt ⁴

Wiebke Ewert ¹

Dominik Oberthür ¹

Oleksandr Yefanov ¹

Susanne Meier ^{5, 6}

Kristina Lorenzen ⁷

Boris Krichel ⁸

Janine-Denise Kopicki ⁸

Luca Gelisio ¹

Wolfgang Brehm ¹

Ilona Dunkel ⁹

Brandon Seychell ¹⁰

Henry Gieseler ^{5, 6}

Brenna Norton Baker ^{11, 12}

Beatriz Escudero-Pérez ²

Martin Domaracky ¹

Sofiane Saouane ¹³

Alexandra Tolstikova ¹

Thomas A. White ¹

Anna Hänle ¹

Michael Groessler ¹

Holger Fleckenstein ¹

Fabian Trost ¹

Marina Galchenkova ¹

Yaroslav Gevorkov ^{1, 14}

Chufeng Li ¹

Salah Awel ¹

Ariana Peck ¹⁵

Miriam Barthelmess ¹

Frank Schlünzen ¹

P. Lourdu Xavier ^{1, 11}

Nadine Werner ¹⁶

Hina Andaleeb ¹⁶

Najeeb Ullah ¹⁶

Sven Falke ¹⁶

Vasundara Srinivasan ¹⁶

Bruno Alves França ¹⁶

Martin Schwinzer ¹⁶

Hévila Brognaro ¹⁶

Cromarte Rogers ^{5, 6}

Diogo Melo ^{5, 6}

Joanna J Zaitseva Doyle ^{5, 6}

Juraj Knoska ¹

Gisel E Peña Murillo ¹

Aida Rahmani Mashhour ¹

V. Hennicke ¹

Pontus Fischer ¹

Johanna Hakanpää ¹³

Jan Meyer ¹³

Philip Gribbon ¹⁷

Bernhard Ellinger ¹⁷

Maria Kuzikov ¹⁷

Markus Wolf ¹⁷

Andrea R Beccari ¹⁸

Gleb Bourenkov ¹⁹

David von Stetten ¹⁹

Guillaume Pompidor ¹⁹

Isabel Bento ¹⁹

Saravanan Panneerselvam ¹⁹

Ivars Karpics ¹⁹

Thomas Schneider ¹⁹

Maria Marta Garcia Alai ¹⁹

Stephan Niebling ¹⁹

Christian Gunther ¹⁹

Christina Schmidt ⁷

Robin Schubert ⁷

Huijong Han ⁷

Juliane Boger ²⁰

Diana C. F. Monteiro ²¹

Linlin Zhang ^{20, 22}

Xinyuanyuan Sun ^{20, 22}

Jonathan Pletzer Zelgert ⁴

Jan Wollenhaupt ²³

Christian Feiler ²³

M Weiss ²³

Eike Schulz ¹¹

Pedram Mehrabi ¹¹

Katarina Karničar ^{24, 25}

Aleksandra Usenik ^{24, 25}

Jure Loboda ²⁴

Henning Tidow ^{5, 26}

Ashwin Chari ²⁷

Rolf Hilgenfeld ^{20, 22}

Charlotte Uetrecht ⁸

Russell J. Cox ²⁸

Andrea Zaliani ¹⁷

Tobias Beck ^{5, 10}

Matthias Rarey ⁴

Stephan Günther ²

D. C. TURK ^{24, 25}

Winfried Hinrichs ^{16, 29}

H. Chapman ^{1, 5, 30}

Arwen R Pearson ^{5, 6}

Christian Betzel ^{5, 16}

Alke Meents ¹

Hide authors affiliations Show authors affiliations: 30 affiliations

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

Deutsches Elektronen-Synchrotron

Center for Free-Electron Laser Science

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

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.

Hamburg University

Deutsches Elektronen-Synchrotron

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.

Deutsches Elektronen-Synchrotron

European Molecular Biology Laboratory

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.

University of Lübeck

German Center for Infection Research

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. |

Publication type: Journal Article

Publication date: 2021-05-07

American Association for the Advancement of Science (AAAS)

Science

scimago Q1

wos Q1

SJR: 10.416

CiteScore: 48.4

Impact factor: 45.8

ISSN: 00368075, 10959203

DOI: 10.1126/science.abf7945

Copy DOI

PubMed ID: 33811162

Multidisciplinary

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, Mpro, 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 Mpro. 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 A repurposed drug-library screen reveals two allosteric drug binding sites of the SARS-CoV-2 main protease. 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.

Found

3 citations

Yarovaya Olga

PhD in Chemistry

117 publications, 1 788 citations, 14 reviews

h-index: 23

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences

3 citations

Baev Dmitry

PhD in Biological/biomedical sciences

68 publications, 973 citations

h-index: 19

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences

3 citations

Chirkova Varvara

24 publications, 129 citations

h-index: 6

Altai State University

3 citations

Belenkaya Svetlana

PhD in Biological/biomedical sciences

39 publications, 263 citations

h-index: 9

State Research Center of Virology and Biotechnology VECTOR

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences

2 citations

Vatsadze Sergey

DSc in Chemistry, professor, professor of the Russian Academy of Sciences

169 publications, 2 094 citations, 9 reviews

h-index: 20

N.D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences

Research interests

Supramolecular chemistry

2 citations

Dhamotharan Karthikeyan

13 publications, 307 citations

h-index: 7

Goethe University Frankfurt

Research interests

Biochemistry

Biophysics

RNA-protein interactions

Structural Biology

1 citation

Fedorov Alexey

DSc in Chemistry, associate member of the Russian Academy of Sciences

93 publications, 2 810 citations, 10 reviews

h-index: 27

Lobachevsky State University of Nizhny Novgorod

1 citation

Osolodkin Dmitry

🥼 🤝

PhD in Chemistry

80 publications, 1 707 citations

h-index: 22

Sechenov First Moscow State Medical University

M.P. Chumakov Federal Scientific Center for Research and Development of Immunobiological Drugs of the Russian Academy of Sciences

1 citation

Medved’ko Aleksei

🥼 🤝

PhD in Chemistry

62 publications, 730 citations, 8 reviews

h-index: 14

N.D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences

Photochemistry Center

1 citation

Mikhailov Anatolii

8 publications, 107 citations

h-index: 4

Moscow Institute of Physics and Technology

1 citation

Gushchin Ivan

🥼 🤝

PhD in Physics and Mathematics

90 publications, 2 094 citations, 18 reviews

h-index: 25

Moscow Institute of Physics and Technology

The structure of proteins

1 citation

Ryzhykau Yury

42 publications, 389 citations, 3 reviews

h-index: 12

Moscow Institute of Physics and Technology

Joint Institute for Nuclear Research

1 citation

Fomina Anastasiia

5 publications, 20 citations

h-index: 3

Lomonosov Moscow State University

M.P. Chumakov Federal Scientific Center for Research and Development of Immunobiological Drugs of the Russian Academy of Sciences

Research interests

Medicinal Chemistry

1 citation

Abdalla Mohnad

🥼 🤝

DSc in Biological/biomedical sciences, associate professor

175 publications, 2 520 citations, 2 196 reviews

1 citation

Mozhaitsev Evgenii

PhD in Chemistry

26 publications, 267 citations

h-index: 11

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences

1 citation

Yüce Merve

7 publications, 61 citations

h-index: 4

Istanbul Technical University

Top-30

Journals

	2 4 6 8 10 12 14 16
Journal of Chemical Information and Modeling	Journal of Chemical Information and Modeling, 15, 4.82% Journal of Chemical Information and Modeling 15 publications, 4.82%
European Journal of Medicinal Chemistry	European Journal of Medicinal Chemistry, 9, 2.89% European Journal of Medicinal Chemistry 9 publications, 2.89%
Journal of Medicinal Chemistry	Journal of Medicinal Chemistry, 9, 2.89% Journal of Medicinal Chemistry 9 publications, 2.89%
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 9, 2.89% International Journal of Molecular Sciences 9 publications, 2.89%
Scientific Reports	Scientific Reports, 8, 2.57% Scientific Reports 8 publications, 2.57%
bioRxiv	bioRxiv, 8, 2.57% bioRxiv 8 publications, 2.57%
Nature Communications	Nature Communications, 7, 2.25% Nature Communications 7 publications, 2.25%
International Journal of Biological Macromolecules	International Journal of Biological Macromolecules, 7, 2.25% International Journal of Biological Macromolecules 7 publications, 2.25%
Journal of Biomolecular Structure and Dynamics	Journal of Biomolecular Structure and Dynamics, 6, 1.93% Journal of Biomolecular Structure and Dynamics 6 publications, 1.93%
eLife	eLife, 5, 1.61% eLife 5 publications, 1.61%
Molecules	Molecules, 5, 1.61% Molecules 5 publications, 1.61%
Angewandte Chemie - International Edition	Angewandte Chemie - International Edition, 5, 1.61% Angewandte Chemie - International Edition 5 publications, 1.61%
Angewandte Chemie	Angewandte Chemie, 5, 1.61% Angewandte Chemie 5 publications, 1.61%
Frontiers in Chemistry	Frontiers in Chemistry, 4, 1.29% Frontiers in Chemistry 4 publications, 1.29%
Viruses	Viruses, 4, 1.29% Viruses 4 publications, 1.29%
Communications Biology	Communications Biology, 4, 1.29% Communications Biology 4 publications, 1.29%
Computational and Structural Biotechnology Journal	Computational and Structural Biotechnology Journal, 4, 1.29% Computational and Structural Biotechnology Journal 4 publications, 1.29%
Antiviral Research	Antiviral Research, 4, 1.29% Antiviral Research 4 publications, 1.29%
Journal of Molecular Biology	Journal of Molecular Biology, 4, 1.29% Journal of Molecular Biology 4 publications, 1.29%
ChemMedChem	ChemMedChem, 4, 1.29% ChemMedChem 4 publications, 1.29%
Biomolecules	Biomolecules, 3, 0.96% Biomolecules 3 publications, 0.96%
Frontiers in Molecular Biosciences	Frontiers in Molecular Biosciences, 3, 0.96% Frontiers in Molecular Biosciences 3 publications, 0.96%
ChemBioChem	ChemBioChem, 3, 0.96% ChemBioChem 3 publications, 0.96%
ACS Omega	ACS Omega, 3, 0.96% ACS Omega 3 publications, 0.96%
RSC Advances	RSC Advances, 3, 0.96% RSC Advances 3 publications, 0.96%
Chemical Communications	Chemical Communications, 3, 0.96% Chemical Communications 3 publications, 0.96%
ChemistrySelect	ChemistrySelect, 3, 0.96% ChemistrySelect 3 publications, 0.96%
Structure	Structure, 3, 0.96% Structure 3 publications, 0.96%
Acta Crystallographica Section D: Structural Biology	Acta Crystallographica Section D: Structural Biology, 2, 0.64% Acta Crystallographica Section D: Structural Biology 2 publications, 0.64%
	2 4 6 8 10 12 14 16

Publishers

	10 20 30 40 50 60 70
Elsevier	Elsevier, 61, 19.61% Elsevier 61 publications, 19.61%
American Chemical Society (ACS)	American Chemical Society (ACS), 47, 15.11% American Chemical Society (ACS) 47 publications, 15.11%
Cold Spring Harbor Laboratory	Cold Spring Harbor Laboratory, 35, 11.25% Cold Spring Harbor Laboratory 35 publications, 11.25%
Wiley	Wiley, 33, 10.61% Wiley 33 publications, 10.61%
Springer Nature	Springer Nature, 32, 10.29% Springer Nature 32 publications, 10.29%
MDPI	MDPI, 27, 8.68% MDPI 27 publications, 8.68%
Taylor & Francis	Taylor & Francis, 14, 4.5% Taylor & Francis 14 publications, 4.5%
Royal Society of Chemistry (RSC)	Royal Society of Chemistry (RSC), 13, 4.18% Royal Society of Chemistry (RSC) 13 publications, 4.18%
Frontiers Media S.A.	Frontiers Media S.A., 10, 3.22% Frontiers Media S.A. 10 publications, 3.22%
International Union of Crystallography (IUCr)	International Union of Crystallography (IUCr), 5, 1.61% International Union of Crystallography (IUCr) 5 publications, 1.61%
Portland Press	Portland Press, 5, 1.61% Portland Press 5 publications, 1.61%
eLife Sciences Publications	eLife Sciences Publications, 5, 1.61% eLife Sciences Publications 5 publications, 1.61%
American Association for the Advancement of Science (AAAS)	American Association for the Advancement of Science (AAAS), 3, 0.96% American Association for the Advancement of Science (AAAS) 3 publications, 0.96%
American Society for Microbiology	American Society for Microbiology, 3, 0.96% American Society for Microbiology 3 publications, 0.96%
SAGE	SAGE, 2, 0.64% SAGE 2 publications, 0.64%
American Society for Biochemistry and Molecular Biology	American Society for Biochemistry and Molecular Biology, 2, 0.64% American Society for Biochemistry and Molecular Biology 2 publications, 0.64%
Proceedings of the National Academy of Sciences (PNAS)	Proceedings of the National Academy of Sciences (PNAS), 2, 0.64% Proceedings of the National Academy of Sciences (PNAS) 2 publications, 0.64%
EDP Sciences	EDP Sciences, 1, 0.32% EDP Sciences 1 publication, 0.32%
Akademiai Kiado	Akademiai Kiado, 1, 0.32% Akademiai Kiado 1 publication, 0.32%
World Scientific	World Scientific, 1, 0.32% World Scientific 1 publication, 0.32%
Public Library of Science (PLoS)	Public Library of Science (PLoS), 1, 0.32% Public Library of Science (PLoS) 1 publication, 0.32%
Microbiology Society	Microbiology Society, 1, 0.32% Microbiology Society 1 publication, 0.32%
Oxford University Press	Oxford University Press, 1, 0.32% Oxford University Press 1 publication, 0.32%
	10 20 30 40 50 60 70

We do not take into account publications without a DOI.
Statistics recalculated weekly.

Are you a researcher?

Create a profile to get free access to personal recommendations for colleagues and new articles.

PDF

Metrics

311

Cite this

GOST |

Cite this

GOST Copy

Günther S. et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease // Science. 2021. Vol. 372. No. 6542. pp. 642-646.

GOST all authors (up to 50) Copy

Günther S. et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease // Science. 2021. Vol. 372. No. 6542. pp. 642-646.

RIS |

Cite this

RIS

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2021_Günther,

author = {Sebastian Günther and Patrick Reinke and Yaiza Fernández García and Julia Lieske and T.M. Lane and Helen Mary Ginn and Faisal H. M. Koua and Christiane Ehrt and Wiebke Ewert and Dominik Oberthür 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-Pérez and Martin Domaracky and Sofiane Saouane and Alexandra Tolstikova and Thomas A. White and Anna Hänle 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 Schlünzen and P. Lourdu Xavier and Nadine Werner and Hina Andaleeb and Najeeb Ullah and Sven Falke and Vasundara Srinivasan and Bruno Alves França and Martin Schwinzer and Hévila Brognaro and Cromarte Rogers and Diogo Melo and Joanna J Zaitseva Doyle and Juraj Knoska and others},

title = {X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease},

journal = {Science},

year = {2021},

volume = {372},

publisher = {American Association for the Advancement of Science (AAAS)},

month = {may},

url = {https://doi.org/10.1126/science.abf7945},

number = {6542},

pages = {642--646},

doi = {10.1126/science.abf7945}

}

MLA

Cite this

MLA Copy

Günther, Sebastian, et al. “X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.” Science, vol. 372, no. 6542, May. 2021, pp. 642-646. https://doi.org/10.1126/science.abf7945.

Publisher

American Association for the Advancement of Science (AAAS)

Journal

Science

scimago Q1

wos Q1

SJR

10.416

CiteScore

48.4

Impact factor

45.8

ISSN

00368075 (Print)

10959203 (Electronic)

Profiles