Peptidomimetic antagonists to the integrin receptor alpha(v)beta(3) will be developed as therapeutics to treat diabetic retinopathy. This disease afflicts 2.1 million people a year and is the leading cause of blindness in the under 55 age group. The only treatment at this time is laser surgery. Integrin alpha(v)beta(3) antagonists represent a new type of non-surgical therapy. The mechanism by which the antagonists will work is by attenuating uncontrolled neovascularization by inhibition of angiogenesis. Using the structural data obtained during Phase I of this study as a starting model, we will design and synthesize peptidomimetics. In our rational design approach we will employ NMR studies on 15N labeled alpha(v)beta(3) selective peptides bound to the receptor, traditional structure activity relationship studies and computer simulations. We will express the alpha(v)beta(3) receptor in a soluble form which facilitates both NMR studies and binding assays. A parallel synthesis approach will be pursued to obtain small targeted families of compounds which will be assayed for their binding to the integrin receptors, and promising leads will be tested in vivo. The goal is the development of drug candidates that will have the proper bioavailability and pharmacokinetics to be useful as therapeutics. PROPOSED COMMERCIAL APPLICATIONS: Non-peptidic integrin alpha(v)beta(3) antagonists will be used to treat diabetic retinopathy, a disease that afflicts 2.1 million people a year and is the leading cause of blindness in the under 55 age group
