Site-selective cleavage of peptides and proteins targeting aromatic amino acid residues

The site-selective cleavage of peptides and proteins at specific amino acid residues is an important strategy for the modification of biomolecules as it can potentially transmute the reactivity profile of the whole molecule. Moreover, precise cleavage of a specific amide bond in peptides and proteins has enormous applications in the domains of chemical biology, genetics, and protein engineering. Among the 20 proteinogenic amino acids, tryptophan (Trp, W), tyrosine (Tyr, Y), phenylalanine (Phe, F) and histidine (His, H) are classified as aromatic amino acids that maintain the function of protein folding through hydrophobic and π-π interactions. Thus, scissoring at a specific site of an aromatic amino acid may alter the structure and function of a peptide or protein. In the last 60-70 years, great success has been achieved in the development of methods for the aromatic amino acid (AAA)-selective cleavage of peptides and proteins. Generally, aromatic side chains are derivatized in the presence of specific reagents. Consequently, either the downstream or the upstream amide bond of the aromatic side chain is activated, and hydrolysis of the amide bond splits the peptide. Unfortunately, a systematic review covering this methodological development of the AAA-selective fission of peptide is lacking to date. Thus, in this review, we aim to showcase the up-to-date progress in the site-selective rupture of peptide bonds at aromatic amino acid residues with an emphasis on the postulated mechanisms, enabling future researchers to further drive progress in this research field.