Synthetic and Biological Studies of Chondroitin Sulfate Oligosaccharides and Glycopeptides

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Xuefei Huang from Michigan State University to study the synthesis and functions of chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG). Carbohydrates play important roles in many biological processes. However, due to the lack of uniformity of complex carbohydrate structures in nature, it has been very challenging to thoroughly understand their function. This project will focus on one specific class of carbohydrates referred to as chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG), chondroitin sulfate that is bonded to protein. New synthetic approaches will be developed to produce these complex molecules, which will greatly expand the range of structures that can be accessed through chemical synthesis. With these materials, it will be possible to establish the impact of different structures on the interactions of CS and CSPG with, for example, amyloid beta peptide, the precursor to the aggregates and plaques that are present in the brains of people with Alzheimer's disease. In addition, the engagement of graduate, undergraduate and high school researchers in this project will provide them with opportunities to be trained in the important and challenging field of complex carbohydrate synthesis. The results generated will provide a highlight for the power of synthetic chemistry, and how chemical synthesis can be utilized to address important biological problems. Chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG) are involved in many important biological events including neural development, organ morphogenesis, inflammation, infection and beta amyloid plaque formation. The number and location of O-sulfates in CS and CSPG can significantly influence their biological properties. As naturally existing CS and CSPG contain heterogeneous sulfation patterns, it is highly challenging to decipher the detailed structure function relationship using CS and CSPG isolated from nature. Contradicting results have been reported in the literature. In order to overcome this problem and facilitate biological studies, synthetic methodologies will be developed to produce CS oligosaccharides and CSPG glycopeptides with well-defined sulfation patterns and structures. The utility of these compounds will be demonstrated in the study of CS/CSPG interactions with beta-amyloid peptide to investigate a potential mechanism for the formation of amyloid plaques, a pathological hallmark of Alzheimer's disease.