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

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.

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https://dx.doi.org/10.1101/2020.05.02.043554 (Preprint) Open Access status unknown

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Creators:
Günther, S.¹, Author
Reinke, P. Y. A.¹, Author
Oberthuer, D.¹, Author
Yefanov, O.¹, Author
Ginn, H.¹, Author
Meier, S.¹, Author
Lane, T. J.¹, Author
Lorenzen, K.¹, Author
Gelisio, L.¹, Author
Brehm, W.¹, Author
Dunkel, I.¹, Author
Domaracky, M.¹, Author
Saouane, S.¹, Author
Lieske, J.¹, Author
Ehrt, C.¹, Author
Koua, F.¹, Author
Tolstikova, A.¹, Author
White, T. A.¹, Author
Groessler, M.¹, Author
Fleckenstein, H.¹, Author
Trost, F.¹, AuthorGalchenkova, M.¹, AuthorGevorkov, Y.¹, AuthorLi, C.¹, AuthorAwel, S.¹, AuthorPeck, A.¹, AuthorPaulraj, L. X.¹, AuthorBarthelmess, M.¹, AuthorSchlünzen, F.¹, AuthorWerner, N.¹, AuthorAndaleeb, H.¹, AuthorUllah, N.¹, AuthorFalke, S.¹, AuthorFranca, B. A.¹, AuthorSchwinzer, M.¹, AuthorBrognaro, H.¹, AuthorSeychell, B.¹, AuthorGieseler, H.¹, AuthorMelo, D.¹, AuthorZaitsev-Doyle, J. J.¹, AuthorNorton-Baker, B.², AuthorKnoska, J.¹, AuthorEsperanza, G.¹, AuthorMashhour, A. R.¹, AuthorGuicking, F.¹, AuthorHennicke, V.¹, AuthorFischer, P.¹, AuthorRogers, C.¹, AuthorMonteiro, D. C. F.¹, AuthorHakanpää, J.¹, AuthorMeyer, J.¹, AuthorNoei, H.¹, AuthorGribbon, P.¹, AuthorEllinger, B.¹, AuthorKuzikov, M.¹, AuthorWolf, M.¹, AuthorZhang, L.¹, AuthorSun, X.¹, AuthorPletzer-Zelgert, J.¹, AuthorWollenhaupt, J.¹, AuthorFeiler, C.¹, AuthorWeiss, M.¹, AuthorSchulz, E.-C.², Author Mehrabi, P.², Author Schmidt, C.¹, AuthorSchubert, R.¹, AuthorHan, H.¹, AuthorKrichel, B.¹, AuthorFernández-García, Y.¹, AuthorEscudero-Pérez, B.¹, AuthorGünther, S.¹, AuthorTurk, D.¹, AuthorUetrecht, C.¹, AuthorBeck, T.¹, AuthorTidow, H.¹, AuthorChari, A.¹, AuthorZaliani, A.¹, AuthorRarey, M.¹, AuthorCox, R.¹, AuthorHilgenfeld, R.¹, AuthorChapman, H. N.¹, AuthorPearson, A. R.¹, AuthorBetzel, C.¹, AuthorMeents, A.¹, Author more..

Affiliations:
1external, ou_persistent22
2Miller Group, Atomically Resolved Dynamics Department, Max Planck Institute for the Structure and Dynamics of Matter, Max Planck Society, ou_1938288

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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.

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Language(s): eng - English

Dates: Published Online: 2020-05-04

Publication Status: Published online

Pages: 17

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Rev. Type: No review

Identifiers: DOI: 10.1101/2020.05.02.043554

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