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.; Xavier, P. L.; 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.; G

doi:10.1101/2020.05.02.043554

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bioRxiv · 10.1101/2020.05.02.043554

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

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Abstract

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro 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 Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro 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 Mpro, 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.

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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., Xavier, P. L., 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., G. 2020-05-04. Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease. https://doi.org/10.1101/2020.05.02.043554

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