Details
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 642-646 |
| Seitenumfang | 5 |
| Fachzeitschrift | SCIENCE |
| Jahrgang | 372 |
| Ausgabenummer | 6542 |
| Frühes Online-Datum | 2 Apr. 2021 |
| Publikationsstatus | Veröffentlicht - 7 Mai 2021 |
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 alreadyapproved 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.
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in: SCIENCE, Jahrgang 372, Nr. 6542, 07.05.2021, S. 642-646.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
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 - Fernandez-Garcia, 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-Perez, 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 - Xavier, P. Lourdu
AU - Werner, Nadine
AU - Andaleeb, Hina
AU - Ullah, Najeeb
AU - Falke, Sven
AU - Srinivasan, Vasundara
AU - Franca, Bruno Alves
AU - Schwinzer, Martin
AU - Brognaro, Hevila
AU - Rogers, Cromarte
AU - Melo, Diogo
AU - Zaitseva-Doyle, Joanna J.
AU - Knoska, Juraj
AU - Pena-Murillo, Gisel E.
AU - Mashhour, Aida Rahmani
AU - Hennicke, Vincent
AU - Fischer, Pontus
AU - Hakanpää, Johanna
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 - Karnicar, 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
AU - Meyer, Jan
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 alreadyapproved 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 alreadyapproved 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.
UR - http://www.scopus.com/inward/record.url?scp=85105632553&partnerID=8YFLogxK
U2 - 10.1126/science.abf7945
DO - 10.1126/science.abf7945
M3 - Article
VL - 372
SP - 642
EP - 646
JO - SCIENCE
JF - SCIENCE
SN - 0036-8075
IS - 6542
ER -