Chemical protein synthesis via one-pot multiple peptide ligation strategies

Abstract

Total chemical synthesis of proteins offers both naturally occurring proteins and artificially engineered proteins through single or multiple ligation reactions of synthetic peptide segments. Efficiently repeated peptide ligation steps are key to synthesize proteins with more than 100 amino acid residues, which are normally divided into three or more peptide segments to assemble. One-pot multiple peptide ligation strategies, in which three or more peptide segments are ligated sequentially without purification and isolation of intermediate peptides, have been intensively developed to increase the synthetic efficiency. This chapter describes the concept and mechanism of peptide ligation followed by recent advances of one-pot peptide ligation, by categorizing the direction of the ligation (i.e. C-to-N and N-to-C direction), and especially focusing on the chemistry enabling regioselective and one-by-one ligation of both terminal reactive “middle” peptide segments.