Spatial screening for the identification of the bioactive conformation of integrin ligands

The development of low-molecular-weight, non-peptidic, and orally available drugs starting from a biologically active peptide is one of the great challenges in medicinal chemistry. In the absence of a crystal structure of the receptor, success in mimicking natural peptide ligands with potent non-peptides has been elusive. A systematic stepwise strategy has been developed to accomplish these goals. These include determining the primary amino acid side chain residues required for molecular recognition via an "Ala scan" and the preferred backbone conformation, which can serve as a template for the bioactive conformation. By "spatial screening" the recognition motif is embedded in cyclic hexa- or pentapeptides, whose conformation is controlled by distinct incorporation of turn-inducing d-amino acid. This procedure was demonstrated on the integrin-binding tripeptide motifs RGD and LDT. The bioactive conformation was derived from conformation-activity relations and used for the design of non-peptidic biased libraries. The recently available crystal structure of the αVβ3-integrin head groups with the highly active cyclic peptide developed in our group confirmed the indirectly derived receptor bound conformation and now allows a structure-based design of new integrin ligands. More recently, the head group of the integrin αIIbβ3 in complex with antibodies was also structurally solved. Homology modeling of other related integrins is used to understand and design integrin subtype specificity.