Monika Raj, Kuei-Chien Tang,Jian Cao, Lisa M. Boatner, Linwei Li,Jonathan Farhi, Kendall N. Houk, Jennifer Spangle, Keriann M. Backus
Angewandte Chemie, 2021
Proteome profiling by activated esters identified >9000 ligandable lysines but they are limited as covalent inhibitors due to poor hydrolytic stability. Here we report our efforts to design and discover a new series of Tunable Amine- Reactive lEectrophiles (TAREs) for selective and robust labeling of lysine. The major challenges in developing selective covalent ligands for lysine are the high nucleophilicity of cysteines and poor hydrolytic stability. Our work circumvents these challenges by a unique design of the TAREs that form stable adducts with lysine and on reaction with cysteine generate another reactive electrophiles for lysine. We highlight that TAREs exhibit substantially high hydrolytic stability as compared to the activated esters and are non-cytotoxic thus have the potential to act as covalent ligands. We applied these alternative TAREs for the intracellular labeling of proteins, and for the selective identification of lysines in the human proteome on a global scale.