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Journal Article

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

MPS-Authors
/persons/resource/persons249434

Norton-Baker,  B.
Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society;
Department of Chemistry, UC Irvine;

Paulraj,  L. X.
Center for Free-Electron Laser Science, DESY;
International Max Planck Research School for Ultrafast Imaging & Structural Dynamics (IMPRS-UFAST), Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society;

/persons/resource/persons202768

Schulz,  E.-C.
Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society;

/persons/resource/persons209117

Mehrabi,  P.
Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society;

Fulltext (public)

642.full.pdf
(Publisher version), 2MB

Supplementary Material (public)

suppl.zip
(Supplementary material), 15MB

Citation

Günther, S., Reinke, P. Y. A., Fernández-García, Y., Lieske, J., Lane, T. J., Ginn, H. M., et al. (2021). X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease. Science, 372(6542), 642-646. doi:10.1126/science.abf7945.


Cite as: http://hdl.handle.net/21.11116/0000-0008-3C42-B
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.