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

DOI: 10.1126/science.abf7945

Authors: Sebastian Gunther (DESY) , Patrick Y. A. Reinke (DESY) , Yaiza Fernández-García (Bernhard Nocht Institute for Tropical Medicine) , Julia Lieske (DESY) , Thomas J. Lane (DESY) , Helen M. Ginn (Diamond Light Source) , Faisal H. M. Koua (DESY) , Christiane Ehrt (Universität Hamburg) , Wiebke Ewert (DESY) , Dominik Oberthuer (DESY) , Oleksandr Yefanov (DESY) , Susanne Meier (Universität Hamburg) , Kristina Lorenzen (European XFEL) , Boris Krichel (Leibniz Institute for Experimental Virology) , Janine-Denise Kopicki (Leibniz Institute for Experimental Virology) , Luca Gelisio (DESY) , Wolfgang Brehm (DESY) , Ilona Dunkel (Max Planck Institute for Molecular Genetics) , Brandon Seychell (Universität Hamburg) , Henry Gieseler (Universität Hamburg) , Brenna Norton-Baker (Max Planck Institute for the Structure and Dynamics of Matter; UC Irvine) , Beatriz Escudero-Pérez (Bernhard Nocht Institute for Tropical Medicine) , Martin Domaracky (DESY) , Sofiane Saouane (DESY) , Alexandra Tolstikova (DESY) , Thomas A. White (DESY) , Anna Hänle (DESY) , Michael Groessler (DESY) , Holger Fleckenstein (DESY) , Fabian Trost (DESY) , Marina Galchenkova (DESY) , Yaroslav Gevorkov (DESY; Hamburg University of Technology) , Chufeng Li (DESY) , Salah Awel (DESY) , Ariana Peck (California Institute of Technology) , Miriam Barthelmess (DESY) , Frank Schluenzen (DESY) , Paulraj Lourdu Xavier (DESY; Max Planck Institute for the Structure and Dynamics of Matter) , Nadine Werner (Universität Hamburg) , Hina Andaleeb (Universität Hamburg) , Najeeb Ullah (Universität Hamburg) , Sven Falke (Universität Hamburg) , Vasundara Srinivasan (Universität Hamburg) , Bruno Alves França (Universität Hamburg) , Martin Schwinzer (Universität Hamburg) , Hévila Brognaro (Universität Hamburg) , Cromarte Rogers (Universität Hamburg) , Diogo Melo (Universität Hamburg) , Joanna J. Zaitseva-Doyle (Universität Hamburg) , Juraj Knoska (DESY) , Gisel E. Peña-Murillo (DESY) , Aida Rahmani Mashhour (DESY) , Vincent Hennicke (DESY) , Pontus Fischer (DESY) , Johanna Hakanpää (DESY) , Jan Meyer (DESY) , Philip Gribbon (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)) , Bernhard Ellinger (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)) , Maria Kuzikov (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)) , Markus Wolf (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)) , Andrea R. Beccari (Dompé Farmaceutici SpA) , Gleb Bourenkov (EMBL Outstation Hamburg) , David Von Stetten (EMBL Outstation Hamburg) , Guillaume Pompidor (EMBL Outstation Hamburg) , Isabel Bento (EMBL Outstation Hamburg) , Saravanan Panneerselvam (EMBL Outstation Hamburg) , Ivars Karpics (EMBL Outstation Hamburg) , Thomas R. Schneider (EMBL Outstation Hamburg) , Maria Marta Garcia-Alai (EMBL Outstation Hamburg) , Stephan Niebling (EMBL Outstation Hamburg) , Christian Günther (EMBL Outstation Hamburg) , Christina Schmidt (European XFEL) , Robin Schubert (European XFEL) , Huijong Han (European XFEL) , Juliane Boger (University of Lübeck) , Diana C. F. Monteiro (Hauptmann Woodward Medical Research Institute) , Linlin Zhang (University of Lübeck) , Xinyuanyuan Sun (University of Lübeck) , Jonathan Pletzer-Zelgert (Universität Hamburg) , Jan Wollenhaupt (Helmholtz Zentrum Berlin) , Christian G. Feiler (Helmholtz Zentrum Berlin) , Manfred S. Weiss (Helmholtz Zentrum Berlin) , Eike-Christian Schulz (Max Planck Institute for the Structure and Dynamics of Matter) , Pedram Mehrabi (Max Planck Institute for the Structure and Dynamics of Matter) , Katarina Karničar (Jozef Stefan Institute; Centre of excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKEBIP)) , Aleksandra Usenik (Jozef Stefan Institute; Centre of excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKEBIP)) , Jure Loboda (Jozef Stefan Institute) , Henning Tidow (Universität Hamburg) , Ashwin Chari (Max Planck Institute for Biophysical Chemistry) , Rolf Hilgenfeld (University of Lübeck) , Charlotte Uetrecht (Heinrich Pette Institute, Leibniz Institute for Experimental Virology) , Russell Cox (Leibniz University of Hannover) , Andrea Zaliani (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)) , Tobias Beck (Universität Hamburg) , Matthias Rarey (Universität Hamburg) , Stephan Günther (Bernhard Nocht Institute for Tropical Medicine) , Dusan Turk (Jozef Stefan Institute; Centre of excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKEBIP)) , Winfried Hinrichs (Universität Hamburg; Universität Greifswald) , Henry N. Chapman (DESY; Universität Hamburg) , Arwen R. Pearson (Universität Hamburg) , Christian Betzel (Universität Hamburg) , Alke Meents (DESY)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Science

State: Published (Approved)
Published: April 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 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 non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

Diamond Keywords: COVID-19; Viruses

Subject Areas: Biology and Bio-materials, Medicine

Facility: P11 at PETRA III; P13 and P14 at EMBL

Added On: 07/04/2021 10:12

Documents:
science.abf7945.full.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Drug Discovery Life Sciences & Biotech

Technical Tags: