Breaking Down and Building Up: Chemical Tools for the Glycosciences

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Glycans are the most abundant organic molecules on the planet and coat the surface of cells in every known organism. These structures can range in size from simple monosaccharides to extended polysaccharides hundreds of units long. Despite evidence that glycans play critical roles in biology, we still lack a detailed understanding of the molecular mechanisms that link diverse glycan structures to their biological function(s). A major reason for this has been a dearth of available tools to manipulate glycans in the context of live cells. Unlike proteins and nucleic acids, biosynthesis of glycans is not a template-directed process, which limits the toolbox of technologies that are useful for studying these structures. My research program is focused on the design and synthesis of chemical probes and reagents that will enable glycoscientists to better understand the basic biological mechanisms that govern glycan biosynthesis, presentation, and ultimately function. Our approach is to harness synthetic chemistry to create platforms that allow us `break down' and `build up' glycans with a focus on molecular detail. Over the next five-years, we will develop reagents that will allow us to inhibit presentation of challenging-to-probe glycans (O-linked structures), invent a superior synthetic route to access the metabolic precursors (nucelotide diphosphate sugars) required to assemble a broad range of glycan structures, and engineer completely synthetic glycocalyces on living cells that will provide absolute molecular control over surface-displayed glycans. This research program will provide highly-qualified personnel (HQP) with valuable interdisciplinary research experiences as they will not only synthesize sophisticated chemical matter, but also validate this material in biological assays. Our specific aims include: Aim 1: Develop next-generation reagents for inhibiting O-linked glycan biosynthesis Aim 2: Improve access to synthetic nucleotide diphosphate sugars. Aim 3: Expand glycocalyx engineering technologies via on-cell glycopolymer synthesis. Combined, these aims will fill multiple unmet needs in the glycosciences and enable future research activities that deeply probe fundamental biological processes.