Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone 
moiety by the SARS-CoV-2 main protease

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

doi:10.1101/2020.05.02.043554

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Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

MPS-Authors

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

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

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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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https://dx.doi.org/10.1101/2020.05.02.043554
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Citation

Günther, S., Reinke, P. Y. A., Oberthuer, D., Yefanov, O., Ginn, H., Meier, S., et al. (2020). Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease. doi:10.1101/2020.05.02.043554.

Cite as: https://hdl.handle.net/21.11116/0000-0006-61B1-4

Abstract

Here we present the crystal structure of SARS-CoV-2 main protease (M^pro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of M^pro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of M^pro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by M^pro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by M^pro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.