STRUCTURAL STUDIES OF A FAMILY OF HIGH-AFFINITY LIGANDS FOR GPIIB IIIA/

A class of potent orally active cyclic peptide antagonists of the glyc oprotein IIb/IIIa adhesion molecule have been prepared by linking a te trapeptide, RGD-containing sequence between the two ends of a semirigi d linker, m-(aminomethyl)benzoic acid (Mamb). To determine how this am ino acid constrains the conformation of the intervening peptide sequen ce and to shed some light on the receptor-bound conformation of the pe ptide, we examined the solution and solid-state structures of nine cyc lic analogues whose receptor binding constants span approximately 4 or ders of magnitude. The general structure of these analogues is cyclo(X xx-Arg-Gly-Asp-Mamb). The backbone conformations of each compound trac e out a rectangular shape with a beta-turn centered at the Xxx-Arg bon d. In the most potent compounds in this series Xxx is a small, aliphat ic D-amino acid, and N-alpha of the Arg residue is methylated: peptide s containing these features are highly rigid and contain a type II' be ta-turn centered at the D-Abu-N-MeArg dipeptide, a highly extended Gly residue, and a C-7 turn centered at the Asp. Peptides lacking the N-m ethyl group and/or with reversed chirality at Xxx are more flexible. T he N-alpha-methyl group also restricts the conformation of the Arg sid e chain. In addition the aliphatic side chain of the D-amino acid, the N-alpha-methyl of N-MeArg, and the phenyl group of the Mamb linker fo rm a continuous hydrophobic surface, which presumably interacts favora bly with the receptor. Finally, the effects of conformational constrai nts introduced at the Mamb and the Asp residues were investigated to d etermine their effects on receptor binding.