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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;

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引用

Günther, S., Reinke, P. Y. A., Fernández-García, Y., Lieske, J., Lane, T. J., Ginn, H. M., Koua, F. H. M., Ehrt, C., Ewert, W., Oberthuer, D., Yefanov, O., Meier, S., Lorenzen, K., Krichel, B., Kopicki, J.-D., Gelisio, L., Brehm, W., Dunkel, I., Seychell, B., Gieseler, H., Norton-Baker, B., Escudero-Pérez, B., Domaracky, M., Saouane, S., Tolstikova, A., White, T. A., Hänle, A., Groessler, M., Fleckenstein, H., Trost, F., Galchenkova, M., Gevorkov, Y., Li, C., Awel, S., Peck, A., Barthelmess, M., Schlünzen, F., Paulraj, L. X., Werner, N., Andaleeb, H., Ullah, N., Falke, S., Srinivasan, V., Franca, B. A., Schwinzer, M., Brognaro, H., Rogers, C., Melo, D., Zaitsev-Doyle, J. J., Knoska, J., Murillo, G. E. P., Mashhour, A. R., Guicking, F., Hennicke, V., Fischer, P., Hakanpää, J., Meyer, J., Gribbon, P., Ellinger, B., Kuzikov, M., Wolf, M., Beccari, A. R., Bourenkov, G., von Stetten, D., Pompidor, G., Bento, I., Panneerselvam, S., Karpics, I., Schneider, T. R., Alai, M. M. G., Niebling, S., Günther, C., Schmidt, C., Schubert, R., Han, H., Boger, J., Monteiro, D. C. F., Zhang, L., Sun, X., Pletzer-Zelgert, J., Wollenhaupt, J., Feiler, C. G., Weiss, M. S., Schulz, E.-C., Mehrabi, P., Karničar, K., Usenik, A., Loboda, J., Tidow, H., Chari, A., Hilgenfeld, R., Uetrecht, C., Cox, R., Zaliani, A., Beck, T., Rarey, M., Günther, S., Turk, D., Hinrichs, W., Chapman, H. N., Pearson, A.., Betzel, C., & Meents, A. (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.


引用: https://hdl.handle.net/21.11116/0000-0008-3C42-B
要旨
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.