SYNTHESIS AND SCREENING OF LINEAR AND CYCLIC OLIGOCARBAMATE LIBRARIES- DISCOVERY OF HIGH-AFFINITY LIGANDS FOR GPIIB IIIA/

Synthetic methodology has been developed for the generation of large, diverse libraries of ''unnatural'' carbamate oligomers using the ''one bead, one peptide'' method. Using a pool of 27 structurally and funct ionally diverse monomers, one acyclic and two cyclic libraries were sy nthesized and screened for binding to the integrin GPIIb/IIIa. Several classes of oligocarbamate ligands for GPIlb/IIIa were discovered, and two cyclic ligands have activities that are within a factor of 3 of k istrin, a snake venom protein that effectively inhibits platelet aggre gation. Preliminary pharmacokinetic characterization was performed on a-linear oligocarbamate ligand, which was cleared from plasma with a h alf-life of 3.6 min.