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

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 .R.; Betzel, C.; Meents, A.

doi:10.1126/science.abf7945

詳細要約

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

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.

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アイテムのパーマリンク: https://hdl.handle.net/21.11116/0000-0008-3F69-D 版のパーマリンク: https://hdl.handle.net/21.11116/0000-0008-7E09-2

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This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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SUPPLEMENT.pdf(Materials and Methods; Supplementary Text; Figs. S1 to S9; Tables S2, S5, and S6; References), TABLE S1.xlsx (Screened drug repurposing libraries. All tested compounds from the "Fraunhofer IME Repurposing Collection" and the "Safe-in-man" library, including information about tested crystals, obtained high-quality datasets and identified hits.), TABLE S4.xlsx (Summary of X-ray crystallographic data processing and refinement statistics), TABLE S7.xlsx (In silico screening of repurposing library against Mpro. The highest ranked 200 compounds of the virtual screening. The names and HYDE scores of the top ranked molecules are given. The yellow background highlights compounds for which high-quality X-ray data was obtained in the X-ray screening. The green background highlights compounds that were detected in the active site in the X-ray screen. Compounds highlighted in light green show a similar binding mode to the fragment with the PDB ligand ID K0G in complex with pro (PDB ID 5R83). Compounds highlighted in light yellow were reported as being active in other screening studies.), TABLE S3.xlsx (Comprehensive summary sheets of hit compounds. Summary showing electron-density maps, compound interactions with Mpro, detailed compound information, biochemical and cell-based antiviral reduction data.), MDAR REPRODUCIBILITY CHECKLIST.pdf

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Günther, S.¹, 著者
Reinke, P. Y. A.¹, 著者
Fernández-García, Y.¹, 著者
Lieske, J.¹, 著者
Lane, T. J.¹, 著者
Ginn, H. M.¹, 著者
Koua, F. H. M.¹, 著者
Ehrt, C.¹, 著者
Ewert, W.¹, 著者
Oberthuer, D.¹, 著者
Yefanov, O.¹, 著者
Meier, S.¹, 著者
Lorenzen, K.¹, 著者
Krichel, B.¹, 著者
Kopicki, J.-D.¹, 著者
Gelisio, L.¹, 著者
Brehm, W.¹, 著者
Dunkel, I.¹, 著者
Seychell, B.¹, 著者
Gieseler, H.¹, 著者
Norton-Baker, B.^{2, 3}, 著者Escudero-Pérez, B.¹, 著者Domaracky, M.¹, 著者Saouane, S.¹, 著者Tolstikova, A.¹, 著者White, T. A.¹, 著者Hänle, A.¹, 著者Groessler, M.¹, 著者Fleckenstein, H.¹, 著者Trost, F.¹, 著者Galchenkova, M.¹, 著者Gevorkov, Y.¹, 著者Li, C.¹, 著者Awel, S.¹, 著者Peck, A.¹, 著者Barthelmess, M.¹, 著者Schlünzen, F.¹, 著者Paulraj, L. X.^{4, 5}, 著者 Werner, N.¹, 著者Andaleeb, H.¹, 著者Ullah, N.¹, 著者Falke, S.¹, 著者Srinivasan, V.¹, 著者Franca, B. A.¹, 著者Schwinzer, M.¹, 著者Brognaro, H.¹, 著者Rogers, C.¹, 著者Melo, D.¹, 著者Zaitsev-Doyle, J. J.¹, 著者Knoska, J.¹, 著者Murillo, G. E. P.¹, 著者Mashhour, A. R.¹, 著者Guicking, F.¹, 著者Hennicke, V.¹, 著者Fischer, P.¹, 著者Hakanpää, J.¹, 著者Meyer, J.¹, 著者Gribbon, P.¹, 著者Ellinger, B.¹, 著者Kuzikov, M.¹, 著者Wolf, M.¹, 著者Beccari, A. R.¹, 著者Bourenkov, G.¹, 著者von Stetten, D.¹, 著者Pompidor, G.¹, 著者Bento, I.¹, 著者Panneerselvam, S.¹, 著者Karpics, I.¹, 著者Schneider, T. R.¹, 著者Alai, M. M. G.¹, 著者Niebling, S.¹, 著者Günther, C.¹, 著者Schmidt, C.¹, 著者Schubert, R.¹, 著者Han, H.¹, 著者Boger, J.¹, 著者Monteiro, D. C. F.¹, 著者Zhang, L.¹, 著者Sun, X.¹, 著者Pletzer-Zelgert, J.¹, 著者Wollenhaupt, J.¹, 著者Feiler, C. G.¹, 著者Weiss, M. S.¹, 著者Schulz, E.-C.², 著者Mehrabi, P.², 著者Karničar, K.¹, 著者Usenik, A.¹, 著者Loboda, J.¹, 著者Tidow, H.¹, 著者Chari, A.¹, 著者Hilgenfeld, R.¹, 著者Uetrecht, C.¹, 著者Cox, R.¹, 著者Zaliani, A.¹, 著者Beck, T.¹, 著者Rarey, M.¹, 著者Günther, S.¹, 著者Turk, D.¹, 著者Hinrichs, W.¹, 著者Chapman, H. N.¹, 著者Pearson, A .R.¹, 著者Betzel, C.¹, 著者Meents, A.¹, 著者全て表示

所属:
1external, ou_persistent22
2Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_1938288
3Department of Chemistry, UC Irvine, ou_persistent22
4Center for Free-Electron Laser Science, DESY, ou_persistent22
5International Max Planck Research School for Ultrafast Imaging & Structural Dynamics (IMPRS-UFAST), Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_2266714

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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 (M^pro), 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 M^pro. 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.

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言語: eng - English

日付: 投稿: 2020-11-20受理: 2021-03-29オンライン出版: 2021-04-02出版: 2021-05-07

出版の状態: 出版

ページ: 5

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識別子（DOI, ISBNなど）: DOI: 10.1126/science.abf7945

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Grant ID : 101003551

Funding program : Horizon 2020 (H2020)

Funding organization : European Commission (EC)

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Grant ID : 759661

Funding program : Horizon 2020 (H2020)

Funding organization : European Commission (EC)

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出版物名: Science

省略形 : Science

種別: 学術雑誌

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出版社, 出版地: Washington, D.C. : American Association for the Advancement of Science

ページ: - 巻号: 372 (6542) 通巻号: - 開始・終了ページ: 642 - 646 識別子（ISBN, ISSN, DOIなど）: ISSN: 0036-8075
CoNE: https://pure.mpg.de/cone/journals/resource/991042748276600_1

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