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