Studies on the Precise Chemical Synthesis of Human Glycoproteins

Abstract

Abstract Our research group demonstrated the semi-synthesis of complex-type biantennary sialyloligosaccharide-library by means of branch-specific glycosidase and several sialyltransferase reactions toward complex-type H2N-Asn-(biantennary compex-type sialyloligosaccharide)-COOH isolated from egg yolk at over a gram scale. This methodology yielded 35 kinds of homogeneous complex-type oligosaccharides. Using this oligosaccharide library, an efficient Boc solid phase peptide synthesis (SPPS) of acid labile sialylglycopeptide-α-thioester was demonstrated. Our research group showed that the sialoside in which the carboxylic acid is protected with a phenacyl group is stable under strong acidic conditions, and this critical finding enabled us to demonstrate the first Boc-SPPS for the synthesis of a sialylglycopeptide-α-thioester. Using both a synthetic method of sialylglycopeptide-α-thioester and native chemical ligation (NCL), our research group synthesized several glycoproteins such as chemokine MCP-3, three kinds of erythropoietin analogues, and interferon-ß. Our research group also demonstrated a unique synthesis that was an intentional synthesis of homogeneous misfolded glycoproteins bearing M9-high-mannose-type oligosaccharide. This unique synthetic misfolded-glycoprotein is useful for the purpose of uncovering the mechanism of molecular recognition in glycoprotein quality control (GQC) in the endoplasmic reticulum (ER). This account discusses the function of the oligosaccharides of glycoproteins based on our research findings.