Studies on the Synthesis and Biochemistry of Complex Glycans

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Carbohydrates (also called glycans) play pivotal roles in many biological processes. Over the past 20 years my lab has focused on synthesizing glycan-based probes to build understanding of these roles at the molecular level. We have been particularly interested in glycans that coat the surfaces of microbes: bacteria, fungi, parasites and viruses. Our work has had double impact, providing new methods to synthesize glycans and generating novel molecules that are used in fundamental structurefunction studies both by my group and with collaborators. In this Discovery Grant renewal, we extend our work to three new projects. The systems chosen for study combine structurally intriguing molecules with systems and molecules that have not yet seen substantial investigation. The groundbreaking studies proposed here will impact the fields of synthetic carbohydrate chemistry and microbial glycobiology. The three projects to be supported by this grant are: 1. Synthesis of glycans containing highly-branched monosaccharide residues that are found in parasites and viruses. These glycans have not yet been the subject of synthetic investigations. In addition to uncovering the rules' for assembling these complex structures, this work will provide probes for immunochemical studies in my lab and collaborative studies on biosynthesis. Long-term applications of this work include novel vaccines or diagnostics for viral and parasitic infections, and compounds for treating viral diseases. 2. Synthesis of glycans from the organism that causes tuberculosis, Mycobacterium tuberculosis, and their evaluation as substrates for arabinanases. These enzymes are involved in degrading key mycobacterial carbohydrates called arabinans. This work will lead to novel substrates and assays for these enzymes, which are potential targets for new classes of anti-mycobacterial agents. 3. Synthesis of glycans related to polysaccharides found in Streptococcus suis, a costly pathogen for the pig industry and an organism that increasingly leads to human infections. These S. suis glycans, which have not previously received the attention of synthetic chemists, will be used in fundamental immunological studies with collaborators. A long-term goal is to design effective vaccines and diagnostic tests for these infections, both for animals and humans. The planned projects will train six graduate students and one undergraduate each year. All trainees will gain skills in synthetic chemistry and characterization of organic molecules. In some projects, they will gain specialized skills in assay development or immunology (in my group or with collaborators). They will work in an environment that has been highly successful in training individuals for careers in the natural sciences and engineering, by combining research training with professional development opportunities tailored to each individual's career objectives.