Novel ionic-based tools for glycoscience

Cell surface carbohydrates offer tremendous unexploited potential as molecular fingerprints that can distinguish disease cells from normal cells. However, cell-surface glycans are extraordinarily challenging molecules to characterize, requiring major investments in highly specialized technology and expertise and that is precisely why their full potential has not yet been realized. Developing the tools that will make the study of cell surface carbohydrates possible, offers the possibility of developing early diagnostic tests, as well as new therapeutic targets and vaccines. Despite the importance of these complex molecules, the synthesis of structurally defined complex carbohydrates is still a very laborious process that requires a high level of technical expertise. This lack of rapid, high throughput synthetic methodologies to provide pure products has hampered progress in glycobiology research, which has had to rely on either isolated materials or traditional, lengthy, target-oriented oligosaccharide synthesis. This is a multidisciplinary project involving synthetic organic chemists, glycobiologists, enzymologists and molecular biologists. The proposal centers on the chemical and enzymatic synthesis of novel O-glycan tools following the methodology recently developed within our team, whereby a versatile ionic tag based "catch-and-release" strategy that requires no chromatography after each reaction step, and that is compatible with chemical and enzymatic oligosaccharide synthetic protocols will be employed. The novel oligosaccharide probes will be used for the study of the O-glycosylation patterns of gastrointestinal and ocular mucins that are relevant to disease. We are addressing a timely problem - lack of O-glycan probes for study - while developing the synthetic tools to make oligosaccharide synthesis available to main stream chemists.

This is a multidisciplinary project involving synthetic organic chemists, glycobiologists, enzymologists, material scientists and molecular biologists. The proposal centres on the chemical and enzymatic synthesis of novel tools to be used as oligosaccharide probes for the study of the glycosylation patterns of gastrointestinal and ocular mucins that are relevant to disease, while concomitantly developing a novel methodology for the general automated synthesis of oligosaccharides.

Carbohydrates and their glycoconjugates are one of the most important classes of marcrobiomolecules in nature which play key structural and functional roles in a diverse range of biological recognition processes. There is a growing global interest in deciphering the human "glycome" or set of carbohydrates in the human body. However, cell-surface glycans are extraordinarily challenging molecules to characterize, requiring major investments in highly specialized technology and expertise and that is precisely why their full potential has not yet been realized.

Developing the tools that will make the study of cell-surface carbohydrates possible for the glycobiology community, offers the possibility of developing early diagnostic, tests as well as new therapeutic targets and vaccines. When unique glycan markers for disease are found, researchers can develop antibodies and drugs that specifically target cells bearing these glycans while sparing healthy tissue and more importantly researchers have the potential to develop tests that allow specific illnesses to be diagnosed early, when treatment is most likely to be effective. That will also have an economic impact in the health care system.

The lack of general and expedient synthetic methodologies to provide pure oligosaccahrides has hampered progress in glycobiology research and it is also one of the main reasons why glycosynthesis is very limited in drug discovery. Developing the synthetic methodologies to make oligosaccharide synthesis available to main stream chemists will have an initial impact in academia and in due course begin to attract significant interest from both the pharmaceutical and fine chemicals sectors from a synthetic and biological point of view.

Thus, the project provides substantial short-term and longer-term outputs of great interests not only for the glycoscience community but for the industry sector and more generally public health.