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

doi:10.1126/science.abf7945

GSTDTAP > 气候变化

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 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
	2021-05-07
发表期刊	Science
出版年	2021
英文摘要	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][1] 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. [1]: /lookup/doi/10.1126/science.abf7945
领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：196[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/325945
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Sebastian Günther,Patrick Y. A. Reinke,Yaiza Fernández-García,et al. X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease[J]. Science,2021.
APA	Sebastian Günther.,Patrick Y. A. Reinke.,Yaiza Fernández-García.,Julia Lieske.,Thomas J. Lane.,...&Alke Meents.(2021).X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.Science.
MLA	Sebastian Günther,et al."X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease".Science (2021).