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Bioinspired Thiophosphorodichloridate Reagents for Chemoselective Histidine Bioconjugation

Author:
Jia, Shang, He, Dan, Chang, Christopher J.
Source:
Journal of the American Chemical Society 2019 v.141 no.18 pp. 7294-7301
ISSN:
1520-5126
Subject:
Lewis bases, arginine, chemical bonding, chemoselectivity, cycloaddition reactions, cysteine, histidine, lysine, phosphorylation, proteins
Abstract:
Site-selective bioconjugation to native protein residues is a powerful tool for protein functionalization, with cysteine and lysine side chains being the most common points for attachment owing to their high nucleophilicity. We now report a strategy for histidine modification using thiophosphorodichloridate reagents that mimic post-translational histidine phosphorylation, enabling fast and selective labeling of protein histidines under mild conditions where various payloads can be introduced via copper-assisted alkyne–azide cycloaddition (CuAAC) chemistry. We establish that these reagents are particularly effective at covalent modification of His-tags, which are common motifs to facilitate protein purification, as illustrated by selective attachment of polyarginine cargoes to enhance the uptake of proteins into living cells. This work provides a starting point for probing and enhancing protein function using histidine-directed chemistry.
Agid:
6427249