Expanding Native Chemical Ligation Methodology with Synthetic Amino Acid Derivatives

Native chemical ligation represents one of the most important technologies for accessing peptides and proteins by chemical synthesis, including those bearing modified amino acids. The development of desulfurization chemistry that enables the conversion of cysteine residues to alanine residues has greatly expanded the scope of ligation chemistry, whereby ligation at 15 of the 20 proteinogenic amino acids is now possible through the incorporation of synthetic thiol-derived amino acids into peptide fragments. More recently, this concept has been further expanded to the 21st amino acid selenocysteine, and selenated amino acid derivatives, under a reaction manifold called the diselenide-selenoester ligation. These ligation reactions proceed with enhanced kinetics compared to native chemical ligation and can be used with a chemoselective deselenization step to access a range of protein targets.