Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments

Petri, László and Ábrányi-Balogh, Péter and Imre, Tímea and Pálfy, Gyula and Perczel, András and Nyíri, Kinga and G. Vértessy, Beáta and Keserű, György M. (2021) Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments. CHEMBIOCHEM. pp. 1-21. ISSN 1439-4227 (print); 1439-7633 (online)

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Abstract

Targeted covalent inhibition and the use of irreversible chemical probes are important strategies in chemical biology and drug discovery. To date, the availability and reactivity of cysteine residues amenable for covalent targeting have been evaluated by proteomic and computational tools. Herein, we present a toolbox of fragments containing a 3,5-bis(trifluoromethyl)phenyl core that was equipped with chemically diverse electrophilic warheads showing a range of reactivities. We characterized the library members for their reactivity,aqueous stability and specificity for nucleophilic amino acids. By screening this library against a set of enzymes amenable for covalent inhibition, we showed that this approach experimentally characterized the accessibility and reactivity of targeted cysteines. Interesting covalent fragment hits were obtained for all investigated cysteine-containing enzymes.

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