Decoding the Structure‐Activity Relationships of Glycosaminoglycans in the Brain

Our research integrates organic chemistry with neurobiology to explore molecular mechanisms of neuronal communication in the brain. In particular, we are interested in understanding how specific carbohydrate structures contribute to the formation and strengthening of neuronal connections. Chondroitin sulfate glycosaminoglycans are sulfated polysaccharides attached to proteoglycans and have been implicated in brain development and spinal cord injury. We have developed chemical strategies that permit investigations into the structure‐activity relationships of chondroitin sulfate. Chemical synthesis provides access to chondroitin sulfate molecules bearing specific sulfation patterns found in the mammalian brain. Our studies define a particular sulfated tetrasaccharide as a minimal motif required for neuronal growth‐promoting activity. Alterations to the sulfation pattern or structure of the tetrasaccharide, but not its overall electrostatic charge, abolish biological activity. These findings provide direct evidence that the activity of chondroitin sulfate is controlled at a molecular level through its sulfation pattern. We are currently building on this discovery to establish the fundamental principles of this potential ‘sulfation code’ and to elucidate the mechanisms by which glycosaminoglycans modulate biological processes.