Tailored chondroitin sulfate glycomimetics via a tunable multivalent scaffold for potentiating NGF/TrkA-induced neurogenesis

The challenges inherent in the synthesis of large glycosaminoglycan (GAG) polysaccharides have made chemically accessible multivalent glycoligands a valuable tool in the field of GAG mimetics. However, the difficulty of positioning sulfated sugar motifs at desired sites has hindered efforts to precisely tailor their biofunctions. Here, we achieved precise orientation of sulfated disaccharide motifs by taking advantage of a structurally well-defined polyproline scaffold, and describe systematic explorations into the importance of the spatial arrangement of sulfated sugars along the scaffold backbone in designing multivalent glycoligands. Our protein binding studies demonstrate that the specific conformational display of pendant sugars is central to direct their multivalent interactions with NGF. By employing computational modeling and cellular studies, we have further applied this approach to engineer NGF-mediated signaling by regulating the NGF/TrkA complexation process, leading to enhanced neuronal differentiation and neurite outgrowth of PC12 cells. Our findings offer a promising strategy for the pinpoint engineering of GAG-mediated biological processes and a novel method of designing new therapeutic agents that are highly specific to GAG-associated disease.