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submitted on 24.10.2018 and posted on 25.10.2018by Shang Jia, Christopher Chang
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.