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Bioinspired Thiophosphorodichloridate Reagents for Chemoselective Histidine Bioconjugation

preprint
submitted on 24.10.2018 and posted on 25.10.2018 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.

Funding

NIH (ES 028096), Novartis Institutes for BioMedical Research, Novartis-Berkeley Center for Proteomics and Chemistry Technologies (NB-CPACT)

History

Email Address of Submitting Author

chrischang@berkeley.edu

Institution

University of California - Berkeley

Country

United States

ORCID For Submitting Author

0000-0001-5732-9497

Declaration of Conflict of Interest

no conflict of interest

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in Journal of the American Chemical Society

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