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

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.

DDC Class

500: Naturwissenschaften

Funding Organisations

Deutsche Forschungsgemeinschaft (DFG)

Bundesministerium für Bildung und Forschung (BMBF)

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We acknowledge financial support from the EXSCALATE4CoV EU-H2020 Emergency Project (101003551), the Cluster of Excellence “Advanced Imaging of Matter” of the Deutsche Forschungsgemeinschaft (DFG), EXC 2056 project ID 390715994, the Helmholtz Association Impulse and Networking funds (projects ExNet-0002 and InternLabs-0011 “HIR3X”), the Federal Ministry of Education and Research (BMBF) via projects 05K16GUA, 05K19GU4, 05K20BI1, 05K20FL1, 16GW0277, and 031B0405D, and the Joachim-Herz-Stiftung Hamburg (project
Infecto-Physics). C.E. and M.R. acknowledge financial support from grant HIDSS-0002 DASHH (Data Science in Hamburg, HELMHOLTZ, Graduate School for the Structure of Matter). R.C. is supported by DFG grants INST 187/621-1 and INST 187/686-1. D.T. is supported by the Slovenian Research Agency (research program P1-0048, Infrastructural program IO-0048). B.S. was supported by an Exploration Grant from the Boehringer Ingelheim Foundation. The Heinrich Pette Institute, Leibniz Institute for Experimental Virology was supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health. C.U. and B.K. were supported by EU Horizon 2020 ERC StG-2017 759661, BMBF RTK Struktur 01KI20391, BMBF Visavix 05K16BH1, and the Leibniz Association SAW-2014-HPI-4 grant.

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https://creativecommons.org/licenses/by/4.0/

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