Synthesis and Biological Activity of Chondroitin Sulfate Biopolymers

Citation

Tully, Sarah Erin (2007) Synthesis and Biological Activity of Chondroitin Sulfate Biopolymers. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/c6pj-np35. https://resolver.caltech.edu/CaltechETD:etd-12132006-122200

Abstract

Chondroitin sulfate glycosaminoglycans are ubiquitously expressed linear, sulfated polysaccharides involved in cell growth, neuronal development and spinal cord injury. The different sulfation motifs presented by chondroitin sulfate may regulate its activity, but efforts to understand the precise biological roles of this glycosaminoglycan have been hampered by its complexity and heterogeneity. Here, we report the synthesis of well-defined chondroitin sulfate oligosaccharides through a convergent approach that permits installation of sulfate groups at precise positions along the carbohydrate backbone, biological evaluation of the synthetic molecules, and generation of antibodies that recognize the distinct sulfation motifs.

Using the chondroitin sulfate oligosaccharide library, we demonstrate that specific sulfation patterns act as molecular recognition elements for growth factors, and modulate neuronal growth. We identified a chondroitin sulfate tetrasaccharide, CS-E, which stimulates the growth and differentiation of multiple neuron types. Through use of carbohydrate microarrays, we found that the CS-E tetrasaccharide binds to a variety of proteins involved in promoting neurite outgrowth. A CS-E disaccharide, an unsulfated tetrasaccharide, and three other sulfated tetrasaccharides, CS-A, CS-C, and CS-R, were also investigated, and showed little effect on neurite outgrowth and reduced growth factor binding compared to the CS-E tetrasaccharide. These studies represent the first, direct investigations into the structure-activity relationships of chondroitin sulfate using homogeneous synthetic molecules, define a tetrasaccharide as a minimal motif required for function, and reveal the importance of sulfation in chondroitin sulfate bioactivity.

Thesis Files