Design of Disaccharide Modules for a Programmable One-Pot Synthesis of Building Blocks with LacNAc Repeating Units for Asymmetric N-Glycans

摘要

Poly-N-acetyllactosamines (poly-LacNAc) containing the repeating unit of N-acetyllactosamine (LacNAc, Gal--1, 4-GlcNAc) are a general glycan epitope of glycoconjugates that are often sialylated or fucosylated to exhibit significant biological functions. To explore the biological significance of poly-LacNAc, scientists have made efforts in preparing multi-antennary N-glycans linked with different numbers of LacNAc units via chemical or chemoenzymatic approaches. However, current methods have not met the challenge of producing asymmetric N-glycans with poly-LacNAc extension for further glycosylation. We have developed a strategy to address this issue using a combined programmable one-pot synthesis and enzymatic strategy based on glycosyltransferases to prepare linear poly-LacNAc and derivatives. The one-pot synthesis is carried out with the use of building blocks that have the GlcNAc--(1, 3)-Gal skeleton. The LacNAc repeating units can be deprotected and further glycosylated enzymatically, as illustrated by the galactosyl transferase and -2, 3-sialyltransferase reactions, to add galactose and sialic acid sequentially, to reduce the complexity of protecting group manipulation. In addition, the synthetic LacNAc derivatives contain a temporary PMP protecting group at the anomeric position that can be easily removed and converted into an oligosaccharyl donor such as glycosyl fluoride for the subsequent synthesis of asymmetric N-glycans.