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Bioinspired Thiophosphorodichloridate Reagents for Chemoselective Histidine Bioconjugation
preprintsubmitted on 24.10.2018, 20:50 and posted on 25.10.2018, 13:25 by 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.
NIH (ES 028096), Novartis Institutes for BioMedical Research, Novartis-Berkeley Center for Proteomics and Chemistry Technologies (NB-CPACT)
Email Address of Submitting Authorchrischang@berkeley.edu
InstitutionUniversity of California - Berkeley
ORCID For Submitting Author0000-0001-5732-9497
Declaration of Conflict of Interestno conflict of interest
Read the published paper
in Journal of the American Chemical Society