Warning: This is a preliminary report that has not been peer-reviewed. It should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

Gunther S, Reinke PYA, Oberthuer D, Yefanov O, Ginn H, Meier S, Lane TJ, Lorenzen K, Gelisio L, Brehm W, Dunkel I, Domaracky M, Saouane S, Lieske J, Ehrt C, Koua F, Tolstikova A, White TA, Groessler M, Fleckenstein H, Trost F, Galchenkova M, Gevorkov Y, Li C, Awel S ... Wollenhaupt J, Feiler C, Weiss M, Schulz E, Mehrabi P, Schmidt C, Schubert R, Han H, Krichel B, FernándezGarcía Y, EscuderoPérez B, Günther S, Turk D, Uetrecht C, Beck T, Tidow H, Chari A, Zaliani A, Rarey M, Cox R, Hilgenfeld R, Chapman HN, Pearson AR, Betzel C, Meents A

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 ...

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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.

Date: May. 02, 2020

Status: Preliminary Report

View Source: doi: 10.1101/2020.05.02.043554

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