Expanding the Scope of Native Chemical Ligation in Glycopeptide Synthesis

Glycoprotein is one of the important biopolymer in a biological system. In order to understand the complex correlation between the exact oligosaccharide structure of the glycoprotein and its function, preparation of homogeneous glycoprotein is to be essential. For such a purpose, chemical synthesis is one of the most promising methods to obtain homogeneous glycoproteins. Glycopolypeptide, which is a backbone of glycoprotein and an essential intermediate for glycoprotein synthesis, can be obtained through coupling of peptide and glycopeptide segments because straightforward synthesis of such a long glycopolypeptide is still a challenging task. Native chemical ligation (NCL) is one of the powerful methods for the coupling reaction of peptides, however, despite extensive investigation, NCL has site limitation for the coupling. In this context, we discovered NCL at serine site, where is a highly conserved amino acid residue in glycoproteins. This reaction strategy is owed to conversion reaction of cysteine residue to serine residue after conventional NCL. This conversion reaction is consisted of three steps; S-methylation of cysteine, CNBr reaction to afford O-ester linked peptide, and O to N acyl shift to get native peptide linkage with serine residue. During extensive investigation of the strategy, we found new reaction media for CNBr reaction, which is the key reaction in the strategy. This enabled us to synthesize not only N-linked glycopeptides but also O-linked sialyl glycopeptides. Thus we could demonstrate the usefulness of this new glycopeptide ligation strategy. In this short review, we will introduce our newly developed cysteine to serine conversion reaction which will expand the application of NCL in peptide as well as glycopeptide synthesis.