Sulfonium-Based Activity-Based Probes for Lysine-Selective Protein Profiling under Alkaline Conditions

Abstract

Due to their strong nucleophilicities, nucleophilic lysine and cysteine residues can be easily recognized and modified by electrophilic groups, thus, acting as the targets for covalent ligands or drugs. Therefore, the development of site-specific protein-modification chemistry for various nucleophilic residues has been explored to label proteins selectively for many biological and therapeutic applications. In this study, we constructed a series of sulfonium-based small molecules to react with the amine group of lysine residues by utilizing the strong electrophilicity of sulfonium, resulting in lysine-selective labeling via the formation of classical amide bonds under alkaline conditions (pH 9.0–11.0). After systematic optimization of the labeling conditions, this strategy was utilized for protein labeling across various bacteria’s lysates. Finally, combined with the activity-based protein profiling (ABPP) strategy, we successfully identified and analyzed hundreds of labeled lysine residues in the bacterial proteome.

Key words

sulfonium based - small molecules - lysine-selective labeling - alkaline conditions - activity-based protein profiling - bacterial proteome

Publication History

Received: 05 December 2023

Accepted after revision: 19 February 2024

Article published online:
01 March 2024

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