A novel approach to the design of potent bioactive peptides by incorporation of proline brackets: antiplatelet effects of Arg-Gly-Asp peptides

Abstract

Enhancing the potency of peptides is a critical and important step in the development of peptide drugs. We have proposed that proline residues flanking protein-protein interaction sites perform a structural role in enhancing their interaction [R.M. Kini and H.J. Evans, Biochem. Biophys. Res. Commun. 212 (1995) 1115–1124]. To test this theory, we incorporated proline residues on either or both sides of the interaction site of an antiplatelet peptide, IARGDMNA and determined the inhibitory potency of the peptides in whole blood aggregation. Inclusion of one proline residue, on either the amino or carboxy terminal side of the interaction site, enhances the antiplatelet activity to approximately the same extent (1.5- to 2.5-fold). Incorporation of proline residues on both sides enhances the activity by 7- to 13-fold. This enhancement of the biological activity of the peptide is probably due to a reduction in the number of possible conformations of the peptide, without introducing the rigidity that would accompany cyclization. Incorporation of proline brackets thus provides a novel approach to the design and development of more potent peptide drugs and ligands.