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

Sebastian Günther; Patrick Y A Reinke; Yaiza Fernández-García; 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-Pérez; 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 França; Martin Schwinzer; Hévila Brognaro; Cromarte Rogers; Diogo Melo; Joanna J Zaitseva-Doyle; Juraj Knoska; Gisel E Peña-Murillo; Aida Rahmani Mashhour; Vincent Hennicke; Pontus Fischer; Johanna Hakanpää; Jan Meyer; 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 Karničar; 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

doi:10.1126/science.abf7945

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

Sebastian Günther, Patrick Y A Reinke, Yaiza Fernández-García, 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 GieselerBrenna Norton-Baker, Beatriz Escudero-Pérez, 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 França, Martin Schwinzer, Hévila Brognaro, Cromarte Rogers, Diogo Melo, Joanna J Zaitseva-Doyle, Juraj Knoska, Gisel E Peña-Murillo, Aida Rahmani Mashhour, Vincent Hennicke, Pontus Fischer, Johanna Hakanpää, Jan Meyer, 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 Karničar, 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

278 Citations (Scopus)

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.

Original language	English
Journal	Science
Volume	372
Issue number	6542
Pages (from-to)	642-646
Number of pages	5
ISSN	0961-8368
DOIs	https://doi.org/10.1126/science.abf7945
Publication status	Published - 07.05.2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

2.21-04 Virology

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

Access to Document

10.1126/science.abf7945

Cite this

Günther, S., Reinke, P. Y. A., Fernández-García, Y., Lieske, J., Lane, T. J., Ginn, H. M., Koua, F. H. M., Ehrt, C., Ewert, W., Oberthuer, D., Yefanov, O., Meier, S., Lorenzen, K., Krichel, B., Kopicki, J.-D., Gelisio, L., Brehm, W., Dunkel, I., Seychell, B., ... Meents, A. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science, 372(6542), 642-646. https://doi.org/10.1126/science.abf7945

@article{11f8172205ca41658cc70f5c060ab3e6,

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 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.",

author = "Sebastian G{\"u}nther and Reinke, \{Patrick Y A\} and Yaiza Fern{\'a}ndez-Garc{\'i}a 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-P{\'e}rez 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 \{Lourdu Xavier\}, P and Nadine Werner and Hina Andaleeb and Najeeb Ullah and Sven Falke and Vasundara Srinivasan and Fran{\c c}a, \{Bruno Alves\} and Martin Schwinzer and H{\'e}vila Brognaro and Cromarte Rogers and Diogo Melo and Zaitseva-Doyle, \{Joanna J\} and Juraj Knoska and Pe{\~n}a-Murillo, \{Gisel E\} and Mashhour, \{Aida Rahmani\} and Vincent Hennicke and Pontus Fischer and Johanna Hakanp{\"a}{\"a} and Jan Meyer 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 Karni{\v c}ar 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",

note = "Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.",

year = "2021",

month = may,

day = "7",

doi = "10.1126/science.abf7945",

language = "English",

volume = "372",

pages = "642--646",

journal = "Science",

issn = "0961-8368",

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Günther, S, Reinke, PYA, Fernández-García, Y, Lieske, J, Lane, TJ, Ginn, HM, Koua, FHM, Ehrt, C, Ewert, W, Oberthuer, D, Yefanov, O, Meier, S, Lorenzen, K, Krichel, B, Kopicki, J-D, Gelisio, L, Brehm, W, Dunkel, I, Seychell, B, Gieseler, H, Norton-Baker, B, Escudero-Pérez, B, Domaracky, M, Saouane, S, Tolstikova, A, White, TA, Hänle, A, Groessler, M, Fleckenstein, H, Trost, F, Galchenkova, M, Gevorkov, Y, Li, C, Awel, S, Peck, A, Barthelmess, M, Schlünzen, F, Lourdu Xavier, P, Werner, N, Andaleeb, H, Ullah, N, Falke, S, Srinivasan, V, França, BA, Schwinzer, M, Brognaro, H, Rogers, C, Melo, D, Zaitseva-Doyle, JJ, Knoska, J, Peña-Murillo, GE, Mashhour, AR, Hennicke, V, Fischer, P, Hakanpää, J, Meyer, J, Gribbon, P, Ellinger, B, Kuzikov, M, Wolf, M, Beccari, AR, Bourenkov, G, von Stetten, D, Pompidor, G, Bento, I, Panneerselvam, S, Karpics, I, Schneider, TR, Garcia-Alai, MM, Niebling, S, Günther, C, Schmidt, C, Schubert, R, Han, H, Boger, J, Monteiro, DCF, Zhang, L, Sun, X, Pletzer-Zelgert, J, Wollenhaupt, J, Feiler, CG, Weiss, MS, Schulz, E-C, Mehrabi, P, Karničar, K, Usenik, A, Loboda, J, Tidow, H, Chari, A, Hilgenfeld, R, Uetrecht, C, Cox, R, Zaliani, A, Beck, T, Rarey, M, Günther, S, Turk, D, Hinrichs, W, Chapman, HN, Pearson, AR, Betzel, C & Meents, A 2021, 'X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease', Science, vol. 372, no. 6542, pp. 642-646. https://doi.org/10.1126/science.abf7945

TY - JOUR

T1 - X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

AU - Günther, Sebastian

AU - Reinke, Patrick Y A

AU - Fernández-García, Yaiza

AU - Lieske, Julia

AU - Lane, Thomas J

AU - Ginn, Helen M

AU - Koua, Faisal H M

AU - Ehrt, Christiane

AU - Ewert, Wiebke

AU - Oberthuer, Dominik

AU - Yefanov, Oleksandr

AU - Meier, Susanne

AU - Lorenzen, Kristina

AU - Krichel, Boris

AU - Kopicki, Janine-Denise

AU - Gelisio, Luca

AU - Brehm, Wolfgang

AU - Dunkel, Ilona

AU - Seychell, Brandon

AU - Gieseler, Henry

AU - Norton-Baker, Brenna

AU - Escudero-Pérez, Beatriz

AU - Domaracky, Martin

AU - Saouane, Sofiane

AU - Tolstikova, Alexandra

AU - White, Thomas A

AU - Hänle, Anna

AU - Groessler, Michael

AU - Fleckenstein, Holger

AU - Trost, Fabian

AU - Galchenkova, Marina

AU - Gevorkov, Yaroslav

AU - Li, Chufeng

AU - Awel, Salah

AU - Peck, Ariana

AU - Barthelmess, Miriam

AU - Schlünzen, Frank

AU - Lourdu Xavier, P

AU - Werner, Nadine

AU - Andaleeb, Hina

AU - Ullah, Najeeb

AU - Falke, Sven

AU - Srinivasan, Vasundara

AU - França, Bruno Alves

AU - Schwinzer, Martin

AU - Brognaro, Hévila

AU - Rogers, Cromarte

AU - Melo, Diogo

AU - Zaitseva-Doyle, Joanna J

AU - Knoska, Juraj

AU - Peña-Murillo, Gisel E

AU - Mashhour, Aida Rahmani

AU - Hennicke, Vincent

AU - Fischer, Pontus

AU - Hakanpää, Johanna

AU - Meyer, Jan

AU - Gribbon, Philip

AU - Ellinger, Bernhard

AU - Kuzikov, Maria

AU - Wolf, Markus

AU - Beccari, Andrea R

AU - Bourenkov, Gleb

AU - von Stetten, David

AU - Pompidor, Guillaume

AU - Bento, Isabel

AU - Panneerselvam, Saravanan

AU - Karpics, Ivars

AU - Schneider, Thomas R

AU - Garcia-Alai, Maria Marta

AU - Niebling, Stephan

AU - Günther, Christian

AU - Schmidt, Christina

AU - Schubert, Robin

AU - Han, Huijong

AU - Boger, Juliane

AU - Monteiro, Diana C F

AU - Zhang, Linlin

AU - Sun, Xinyuanyuan

AU - Pletzer-Zelgert, Jonathan

AU - Wollenhaupt, Jan

AU - Feiler, Christian G

AU - Weiss, Manfred S

AU - Schulz, Eike-Christian

AU - Mehrabi, Pedram

AU - Karničar, Katarina

AU - Usenik, Aleksandra

AU - Loboda, Jure

AU - Tidow, Henning

AU - Chari, Ashwin

AU - Hilgenfeld, Rolf

AU - Uetrecht, Charlotte

AU - Cox, Russell

AU - Zaliani, Andrea

AU - Beck, Tobias

AU - Rarey, Matthias

AU - Günther, Stephan

AU - Turk, Dusan

AU - Hinrichs, Winfried

AU - Chapman, Henry N

AU - Pearson, Arwen R

AU - Betzel, Christian

AU - Meents, Alke

PY - 2021/5/7

Y1 - 2021/5/7

N2 - 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.

AB - 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.

U2 - 10.1126/science.abf7945

DO - 10.1126/science.abf7945

M3 - Journal articles

C2 - 33811162

SN - 0961-8368

VL - 372

SP - 642

EP - 646

JO - Science

JF - Science

IS - 6542

ER -

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

Abstract

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Coronavirus related work

Access to Document

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Cite this