Modular Synthesis of N-Glycans and Homogeneous Glycoproteins

The Scripps Research Institute, La Jolla CA

Investigators

Abstract

With this award, the Chemical Synthesis Program of the NSF Division of Chemistry is supporting the research of Professor Chi-Huey Wong at The Scripps Research Institute. Professor Wong and his research team are developing new ways to link sugar molecules to form oligosaccharides (relatively small carbohydrates) using chemical and enzymatic tools. These new methods for the construction of oligosaccharides are then being used to assemble glycoproteins (proteins that have sugars attached to them) and to understand how the oligosaccharide fragments affect protein function. Glycoproteins perform many important biological functions that are central to the immune, digestive, and reproductive systems, for example. Since most proteins in higher organisms are modified with oligosaccharides of varying sequence, length and branching, at multiple loci, there is considerable microheterogeneity for any given glycoprotein. This makes it difficult to establish clear structure/function relationships for glycoproteins. The development of methods for the defined synthesis of oligosaccharides and their use for the assembly of homogeneous glycoproteins is critically important for such studies. The work being done in the Wong group is also providing graduate and undergraduate students, as well as postdoctoral researchers, with interdisciplinary training in chemistry, chemical biology, molecular biology, and biochemistry. Understanding the effect of glycosylation on protein folding, structure and function is vitally important in biology and medicine and requires access to a large number of complex structurally-defined asparagine-linked N-glycans. Professor Wong and his research group are addressing this challenge by designing modular chemoenzymatic methods for assembling oligosaccharides. More specifically, they are developing methods to prepare multi-antennary N-linked glycans with fluorinated sialic acid and fucosylated functionalities, as well as optimizing enzymes to achieve transfers of tri-and tetrantennary oligosaccharides. The significant array of N-glycans being prepared in these studies is then available to generate homogeneous glycoproteins, such as monoclonal antibodies, for the study of their activities. All modules, enzymes, and reagents being discovered are also being made available to the community to provide a useful hybrid synthetic/enzymatic toolbox to facilitate the critical need for better understanding of protein glycosylation and to advance research in glycoscience. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.