Histidine‐Specific Bioconjugation: Expanding the Chemical Biology Toolbox for Protein Modification

ABSTRACT Histidine (His, H) is a proteinogenic amino acid bearing an imidazole side‐chain, which possesses two nitrogen atoms at N(π)‐ and N(τ)‐positions. The nitrogen atoms of the imidazole ring are nucleophilic in nature. They can behave as a base, while their protonated form can serve as an acid. Obviously, the carbon‐atoms situated next to two nucleophilic centers are electrophilic in nature. As a consequence, histidine residues in peptides and proteins can undergo post‐translational modifications applying aza‐Michael additions, Minisci‐type reactions, various C─N coupling strategies etc. and these conjugation‐technologies can be applied in the fields of protein mapping, living cell labelling, purification of protein, and many more. This review aims to spotlight the modern strategies that are utilized for the histidine‐specific bioconjugation of proteins and diverse applications of the protein conjugates. It will also highlight the literature gaps and new opportunities for the sake of future innovation in the research area.