RT Journal Article
SR Electronic
T1 Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.02.043554
DO 10.1101/2020.05.02.043554
A1 Sebastian Günther
A1 Patrick Y. A. Reinke
A1 Dominik Oberthuer
A1 Oleksandr Yefanov
A1 Helen Ginn
A1 Susanne Meier
A1 Thomas J. Lane
A1 Kristina Lorenzen
A1 Luca Gelisio
A1 Wolfgang Brehm
A1 Illona Dunkel
A1 Martin Domaracky
A1 Sofiane Saouane
A1 Julia Lieske
A1 Christiane Ehrt
A1 Faisal Koua
A1 Alexandra Tolstikova
A1 Thomas A. White
A1 Michael Groessler
A1 Holger Fleckenstein
A1 Fabian Trost
A1 Marina Galchenkova
A1 Yaroslav Gevorkov
A1 Chufeng Li
A1 Salah Awel
A1 Ariana Peck
A1 P. Lourdu Xavier
A1 Miriam Barthelmess
A1 Frank Schlünzen
A1 Nadine Werner
A1 Hina Andaleeb
A1 Najeeb Ullah
A1 Sven Falke
A1 Bruno Alves Franca
A1 Martin Schwinzer
A1 Hévila Brognaro
A1 Brandon Seychell
A1 Henry Gieseler
A1 Diogo Melo
A1 Jo J. Zaitsev-Doyle
A1 Brenna Norton-Baker
A1 Juraj Knoska
A1 Gisel Esperanza
A1 Aida Rahmani Mashhour
A1 Filip Guicking
A1 Vincent Hennicke
A1 Pontus Fischer
A1 Cromarte Rogers
A1 Diana C. F. Monteiro
A1 Johanna Hakanpää
A1 Jan Meyer
A1 Heshmat Noei
A1 Phil Gribbon
A1 Bernhard Ellinger
A1 Maria Kuzikov
A1 Markus Wolf
A1 Linlin Zhang
A1 Xinyuanyuan Sun
A1 Jonathan Pletzer-Zelgert
A1 Jan Wollenhaupt
A1 Christian Feiler
A1 Manfred Weiss
A1 Eike-Christian Schulz
A1 Pedram Mehrabi
A1 Christina Schmidt
A1 Robin Schubert
A1 Huijong Han
A1 Boris Krichel
A1 Yaiza Fernández-García
A1 Beatriz Escudero-Pérez
A1 Stephan Günther
A1 Dusan Turk
A1 Charlotte Uetrecht
A1 Tobias Beck
A1 Henning Tidow
A1 Ashwin Chari
A1 Andrea Zaliani
A1 Matthias Rarey
A1 Russell Cox
A1 Rolf Hilgenfeld
A1 Henry N. Chapman
A1 Arwen R. Pearson
A1 Christian Betzel
A1 Alke Meents
YR 2020
UL http://biorxiv.org/content/early/2020/05/04/2020.05.02.043554.abstract
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.Competing Interest StatementThe authors have declared no competing interest.