Synthesis and Screening of Linear and Cyclic Oligocarbamate Libraries. Discovery of High Affinity Ligands for GPIIb/IIIa

Abstract

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 functionally diverse monomers, one acyclic and two cyclic libraries were synthesized and screened for binding to the integrin GPIIb/IIIa. Several classes of oligocarbamate ligands for GPIIb/IIIa were discovered, and two cyclic ligands have activities that are within a factor of 3 of kistrin, a snake venom protein that effectively inhibits platelet aggregation. Preliminary pharmacokinetic characterization was performed on a linear oligocarbamate ligand, which was cleared from plasma with a half-life of 3.6 min.