RATIONAL DESIGN OF ADHESION BLOCKING ANTIINFLAMMATORIES

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The intent of this proposal is to develop potent selecting ligand analogs presented in multivalent "arrays" to suppress inflammation driven pathological disease. There are a variety of both acute and chronic diseases which may be prevented or suppressed by selectin blocking compounds. These include acute diseases such as ischemia-reperfusion injury, acute respiratory distress syndrome, septic shock leading to multiple organ failure and chronic diseases including allergy, autoimmunity, rheumatoid arthritis, insulitis and diabetes. In this proposal, we have two specific aims. First we will measure the blocking potency of a defined group of multimerized selectin ligand analogs functionally expressed on UV-cross-link-stabilized-liposomes. This will consist of examining the effects of multimerized carbohydrate ligands combined with a variety of "auxiliary" non-carbohydrate modifiers that will form "epitope arrays". Through this study, we will develop an understanding of factors responsible for determining effective selectin adhesion blocking by these arrays. Second, we will structurally optimize the most effective inhibitory selectin ligand analogs in terms of percent active epitopes presented, formulation of active and "assisting" ligand components and the overall size of the assembly. These blocking compounds and their refinements will be tested using human leukocyte- endothelial rolling assays and then in animal models of inflammation. PROPOSED COMMERCIAL APPLICATIONS: The discovery and successful construction of selectin blocking compounds that can he fully developed into powerful pharmaceuticals to blunt pathological inflammation will be of enormous value in treating both acute and chronic human disease. Current and projected estimates indicate that effective anti-inflammatory products with broad disease applications could represent more than a billion dollar product market.