We propose to study the conformation in solution of three peptide antagonists towards integrin alpha V beta 3 by NMR spectroscopy. Two peptides contain the RGDDV pentapeptide pharmacophore that selectively binds alpha V beta 3, and the third peptide selectively binds integrins that contain the beta 3 subunit. Orally active antagonists towards the integrin alpha V beta 3 will be useful as therapeutics in the treatment of diabetic retinopathy and rheumatoid arthritis. The mechanism by which the antagonists will work is by attenuating a pathology of the diseases, uncontrolled cell proliferation, by inhibition of angiogenesis. Our peptides have low nanomolar potency towards integrin alpha V beta 3. However, the peptides neither are orally active nor have long enough half lives to be useful in oral administration. Thus, we propose to use the structural information from the NMR studies to design peptidomimetic alpha V beta 3 antagonists that will exhibit the proper pharmacokinetic and pharmacodynamic parameters to treat the two diseases when dosed orally.Proposed commercial application:Orally active integrin alpha V beta 3 antagonists will be used to treat diabetic retinopathy, a disease that affects 2.1 million people a year, and to treat rheumatoid arthritis, a disease that affects 1.2 million people a year.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
