TY  - EJOUR
AU  - Guenther, Sebastian
AU  - Reinke, Patrick
AU  - Oberthuer, Dominik
AU  - Yefanov, Oleksandr
AU  - Ginn, Helen
AU  - Meier, Susanne
AU  - Lane, Thomas
AU  - Lorenzen, Kristina
AU  - Gelisio, Luca
AU  - Brehm, Wolfgang
AU  - Dunkel, Ilona
AU  - Domaracky, Martin
AU  - Saouane, Sofiane
AU  - Lieske, Julia
AU  - Ehrt, Christiane
AU  - Koua, Faisal
AU  - Tolstikova, Alexandra
AU  - White, Thomas
AU  - Groessler, Michael
AU  - Fleckenstein, Holger
AU  - Trost, Fabian
AU  - Galchenkova, Marina
AU  - Gevorkov, Yaroslav
AU  - Li, Chufeng
AU  - Awel, Salah
AU  - Peck, Ariana
AU  - Xavier, P. Lourdu
AU  - Barthelmess, Miriam
AU  - Schlünzen, Frank
AU  - Werner, Nadine
AU  - Andaleeb, Hina
AU  - Ullah, Najeeb
AU  - Falke, Sven
AU  - Franca, Bruno Alves
AU  - Schwinzer, Martin
AU  - Brognaro, Hevila
AU  - Seychell, Brandon
AU  - Gieseler, Henry
AU  - Melo, Diogo
AU  - Zaitsev-Doyle, Jo J.
AU  - Norton-Baker, Brenna
AU  - Knoska, Juraj
AU  - Pena Murillo, Gisel Esperanza
AU  - Mashhour, Aida Rahmani
AU  - Guicking, Filip
AU  - Hennicke, Vincent
AU  - Fischer, Pontus
AU  - Rogers, Cromarte
AU  - Monteiro, Diana C. F.
AU  - Hakanpää, Johanna
AU  - Meyer, Jan
AU  - Noei, Heshmat
AU  - Gribbon, Phil
AU  - Ellinger, Bernhard
AU  - Kuzikov, Maria
AU  - Wolf, Markus
AU  - Zhang, Linlin
AU  - Sun, Xinyuanyuan
AU  - Pletzer-Zelgert, Jonathan
AU  - Wollenhaupt, Jan
AU  - Feiler, Christian
AU  - Weiss, Manfred
AU  - Schulz, Eike-Christian
AU  - Mehrabi, Pedram
AU  - Schmidt, Christina
AU  - Schubert, Robin
AU  - Han, Huijong
AU  - Krichel, Boris
AU  - Fernández-García, Yaiza
AU  - Escudero-Pérez, Beatriz
AU  - Günther, Stephan
AU  - Turk, Dusan
AU  - Uetrecht, Charlotte
AU  - Beck, Tobias
AU  - Tidow, Henning
AU  - Chari, Aschwin
AU  - Zaliani, Andrea
AU  - Rarey, Matthias
AU  - Cox, Russel
AU  - Hilgenfeld, Rolf
AU  - Chapman, Henry N
AU  - Pearson, Arwen R.
AU  - Betzel, Christian
AU  - Meents, Alke
TI  - Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
PB  - Zenodo
M1  - PUBDB-2020-01727
PY  - 2020
N1  - PrePrint: https://www.biorxiv.org/content/10.1101/2020.05.02.043554
AB  - 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.
LB  - PUB:(DE-HGF)25
DO  - DOI:10.1101/2020.05.02.043554
UR  - https://bib-pubdb1.desy.de/record/437962
ER  -