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

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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; Peña-Murillo, Gisel E; Mashhour, Aida Rahmani; Hennicke, Vincent; Fischer, Pontus; Hakanpää, Johanna; Meyer, Jan; Gribbon, Philip; Ellinger, Bernhard; Kuzikov, Maria; Wolf, Markus; Beccari, Andrea R; Bourenkov, Gleb; von Stetten, David; Pompidor, Guillaume; Bento, Isabel; Panneerselvam, Saravanan; Karpics, Ivars; Schneider, Thomas R; Garcia-Alai, Maria Marta; Niebling, Stephan; Günther, Christian; Schmidt, Christina; Schubert, Robin; Han, Huijong; Boger, Juliane; Monteiro, Diana C F; Zhang, Linlin; Sun, Xinyuanyuan; Pletzer-Zelgert, Jonathan; Wollenhaupt, Jan; Feiler, Christian G; Weiss, Manfred S; Schulz, Eike-Christian; Mehrabi, Pedram; Karničar, Katarina; Usenik, Aleksandra; Loboda, Jure; Tidow, Henning; Chari, Ashwin; Hilgenfeld, Rolf; Uetrecht, Charlotte; Cox, Russell; Zaliani, Andrea; Beck, Tobias; Rarey, Matthias; Günther, Stephan; Turk, Dusan; Hinrichs, Winfried; Chapman, Henry N; Pearson, Arwen R; Betzel, Christian; Meents, Alke.

In: SCIENCE, Vol. 372, No. 6542, 07.05.2021, p. 642-646.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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

APA

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

Vancouver

Günther S, Reinke PYA, Fernández-García Y, Lieske J, Lane TJ, Ginn HM et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. SCIENCE. 2021 May 7;372(6542):642-646. https://doi.org/10.1126/science.abf7945

Bibtex

@article{5e35ae636953411581f652cce47f8779,
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.",
keywords = "Allosteric Site, Animals, Antiviral Agents/chemistry, Catalytic Domain, Chlorocebus aethiops, Coronavirus 3C Proteases/antagonists & inhibitors, Crystallography, X-Ray, Drug Development, Drug Evaluation, Preclinical, Protease Inhibitors/chemistry, SARS-CoV-2/drug effects, Vero Cells, Virus Replication/drug effects",
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 = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6542",

}

RIS

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

N1 - Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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.

KW - Allosteric Site

KW - Animals

KW - Antiviral Agents/chemistry

KW - Catalytic Domain

KW - Chlorocebus aethiops

KW - Coronavirus 3C Proteases/antagonists & inhibitors

KW - Crystallography, X-Ray

KW - Drug Development

KW - Drug Evaluation, Preclinical

KW - Protease Inhibitors/chemistry

KW - SARS-CoV-2/drug effects

KW - Vero Cells

KW - Virus Replication/drug effects

U2 - 10.1126/science.abf7945

DO - 10.1126/science.abf7945

M3 - SCORING: Journal article

C2 - 33811162

VL - 372

SP - 642

EP - 646

JO - SCIENCE

JF - SCIENCE

SN - 0036-8075

IS - 6542

ER -