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Assessment of Tractable Cysteines for Covalent Targeting by Screening Covalent Fragments
Author(s) -
Petri László,
ÁbrányiBalogh Péter,
Tímea Imre,
Pálfy Gyula,
Perczel András,
Knez Damijan,
Hrast Martina,
Gobec Martina,
Sosič Izidor,
Nyíri Kinga,
Vértessy Beáta G.,
Jänsch Niklas,
Desczyk Charlotte,
MeyerAlmes FranzJosef,
Ogris Iza,
Golič Grdadolnik Simona,
Iacovino Luca Giacinto,
Binda Claudia,
Gobec Stanislav,
Keserű György M.
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000700
Subject(s) - covalent bond , cysteine , chemistry , combinatorial chemistry , reactivity (psychology) , electrophile , nucleophile , chemical biology , enzyme , amino acid , stereochemistry , biochemistry , organic chemistry , medicine , alternative medicine , pathology , catalysis
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.