Receptor tyrosine kinases and other cell-surface receptors are known to activate signal transduction pathways by ligand-induced dimerization or clustering, resulting in a range of important health-related consequences such as cell proliferation, inflammatory response, and angiogenesis. Receptor clustering is often promoted by heparin-binding proteins complexed onto nearby proteoglycans. This proposal will develop a new class of receptor inhibitors based on a novel concept called anti-clustering, in which nanometer-sized complexes will bind to multiple receptors but retain them in arrested states. Sulfated oligosaccharide ligands will be grafted onto colloidal gold nanoparticles, which will serve as multivalent scaffolds for the selective recruitment and orientation of heparin-binding signaling proteins such as growth factors or chemokines. Synthetic strategies will be developed for functionalizing nanoparticles with orthogonally protected oligosaccharides, which will be deprotected and sulfated in variable order to generate libraries of glycosylated nanoparticles (GNs) with variable sulfation patterns.
Specific Aims i nclude: (1) a robust method for encapsulating nanoparticles in nondesorptive coatings and functionalizing them with orthogonally protected oligosaccharides at low surface densities; (2) orthogonal protecting-group strategies for synthesizing disaccharides with up to 32 different sulfation patterns; (3) generation and characterization of sulfated GN libraries; (4) screening of GNs for highaffinity binding to fibroblast growth factors (FGFs), and their subsequent evaluation as inhibitors (anticlustering agents) against FGF receptor-mediated signal transduction using a cell proliferation assay. ? ?
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