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

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 languageEnglish
JournalScience
Volume372
Issue number6542
Pages (from-to)642-646
Number of pages5
ISSN0961-8368
DOIs
Publication statusPublished - 07.05.2021

Research Areas and Centers

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

DFG Research Classification Scheme

  • 204-04 Virology

Coronavirus related work

  • Research on SARS-CoV-2 / COVID-19

Fingerprint

Dive into the research topics of 'X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease'. Together they form a unique fingerprint.

Cite this