CONCEPT AND PROGRESS IN THE DEVELOPMENT OF RGD-CONTAINING PEPTIDE PHARMACEUTICALS

The cell adhesion domain, arginine-glycine-aspartic acid (RGD), has been incorporated into synthetic peptides to perform either of two modes of drug action, antagonist or agonist. Short, conformationally constrained peptides have been developed as antagonists for the platelet membrane glycoprotein complex, the integrin alpha(IIb)beta(3), using cell-base and integrin-based assays. In combination with a comparative molecular modeling study, these results have helped identify common conformational elements in the pharmacophore of this class of molecules. Peptides are presented that ar highly potent, integrin specific, and that possess reduced pharmacological side effect. Also presented is the development of a peptide that modifies, noncovalently, the surfaces of a wide variety of this molecule is evident from its ability to stimulate cell attachment on these surfaces. This is shown to translate into an in vivo activity of faster and more complete tissue integration, and a reduction in foreign body response. (C) 1995 John Wiley & Sons, Inc.