Protein Chemical Synthesis by Ligation of Peptide Hydrazides

摘要

Protein chemical synthesis can overcome the potential limitations of protein expression and produce proteins with predesigned changes and modifications with atomic precision. Key to the success of modern protein chemical synthesis is the chemoselective ligation reaction. The most successful ligation method is the native chemical ligation developed by Kent etal. It involves a chemoselective reaction between a C-terminal peptide thioester and an N-terminal cysteine (Cys). Both synthetic and recombinant peptides can be used in native chemical ligation. The utility of native chemical ligation has been demonstrated by the total and semisynthesis of a variety of proteins, which enables the broad application of synthetic chemistry to the study of protein biology. Although native chemical ligation is a transformative method, its applicability can sometimes be limited in two respects: 1) peptide thioesters remain challenging to synthesize with Fmoc chemistry; 2) convergent synthesis of larger proteins without using protecting groups requires an "orthogonal" amide-forming ligation chemistry, that is, one that is compatible with the use of native chemical ligation.