SBIR-STTR Award

IL-5 is a T cell derived cytokine involved in the pathogenesis of atopic diseases. It specifically controls the production, activation and localization of eosinophils. Eosinophils are the major cause of tissue damage resulting in the symptoms of asthma and related allergic disorders. Thus, the design of orally bioavailable IL-5 receptor antagonists is an important area of therapeutic research for allergic asthma. Phase 1 of this project includes the following objectives: 1) generation of a 3-D dynamic model of a solvated IL-5; 2) identification of a surface aminoacyl sidechains which participate in ligand-receptor binding to generated pharmacophoric templates; 3) identification of non-peptide chemical that match the template for the described chemical properties; and 4) evaluation of biochemical and pharmacological activities of the selected small molecule IL-5 receptor antagonist candidates. Algorithms and computational tools necessary to derive these compounds have been established and implemented at Structural Bioinformatics inc. the goal of phase 2 activities aimed at refinement of the initial leads into qualified pre-clinical candidates for IL-5 antagonism

IL-5 is an essential cytokine for the maturation of eosinophil precursors to eosinophils, and it is those eosinophils that have been found to correlate with the severity of the late asthmatic reaction. Thus, design of IL-5 receptor antagonists that block pulmonary eosinophil disorders and present a new approach to treating allergic asthma. In Phase I, we used SBI technology to compute a 3-D dynamic model from the crystal structure of IL-5 and construct pharmacophore templates to screen large scale compound libraries in order to identify potential inhibitors of IL-5 action. Three compounds showing Ki greater than 10 uM in an IL-5 receptor plate assays were obtained. The goal of Phase II is to perform computationally guided synthetic optimizations of active lead compounds identified in Phase I and to discover selective and potent drug candidates active in a murine model for allergic asthma. The long term goal of this project is to develop at least one non-peptide IL-5 receptor antagonist as a potential anti-asthmatic and anti-allergic agent.