Revolutionary work in the development of chemical ligation methods enabling protein chemical synthesis includes native chemical ligation (NCL), which relies on the N-terminal cysteine residue to mediate a chemoselective union reaction of two side-chain unprotected peptidesegments with a natural peptidic linkage at the ligation site. Since cysteine is one of the lowest abundant amino acids (1.7% occurrence) in natural polypeptides and proteins, many efforts have been devoted to searching for the chemoselective ligation at other amino acid sites, including a menu of complementary cysteine-free ligation approaches. These methods have provided important additions to the toolbox of chemical ligation. In this study, we describe a 4-hydroxyproline ligation ligation (4-HypL) enabling peptide convergent synthesis. A peptide fragment with a C-terminal salicylaldehyde ester chemoselectively reacts with another side-chain peptidesegment containing an N-terminal 4-hydroxyproline to afford an N,O-benzylidene acetal linked product. The resulting acetal group, upon treatment with acid, is removed to restore the native peptide bond at the ligation site. As serine and threonine residues are very important in natural peptides and proteins 4-HypL should offer new opportunities for convergent protein synthesis.

Development of  4-hydroxyproline ligation  for coupling of peptide fragments

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.