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α‐Methylene‐β‐Lactone Scaffold for Developing Chemical Probes at the Two Ends of the Selectivity Spectrum
Author(s) -
Wang Lei,
Riel Louis P.,
Bajrami Bekim,
Deng Bin,
Howell Amy R.,
Yao Xudong
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.202000605
Subject(s) - chemistry , moiety , glutathione , alkyne , cysteine , lactone , serine , stereochemistry , selectivity , combinatorial chemistry , threonine , biochemistry , enzyme , catalysis
The utilities of an α‐methylene‐β‐lactone (MeLac) moiety as a warhead composed of multiple electrophilic sites are reported. We demonstrate that a MeLac‐alkyne not only reacts with diverse proteins as a broadly reactive measurement probe, but also recruits reduced endogenous glutathione (GSH) to assemble a selective chemical probe of GSH‐β‐lactone (GSH‐Lac)‐alkyne in live cells. Tandem mass spectrometry reveals that MeLac reacts with nucleophilic cysteine, serine, lysine, threonine, and tyrosine residues, through either Michael or acyl addition. A peptide‐centric proteomics platform demonstrates that the proteomic selectivity profiles of orlistat and parthenolide, which have distinct reactivities, are measurable by MeLac‐alkyne as a high‐coverage probe. The GSH‐Lac‐alkyne selectively probes the glutathione S‐transferase P responsible for multidrug resistance. The assembly of the GSH‐Lac probe exemplifies a modular and scalable route to develop selective probes with different recognizing moieties.