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, Jahrgang 372, Nr. 6542, 07.05.2021, S. 642-646.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -