Combinatorial Chemistry Reveals a New Motif That Binds the Platelet Fibrinogen Receptor, gpIIbIIIa

Abstract

Among cell adhesion molecules, the classic Arg-Gly-Asp (RGD) motif is the best studied. We used combinatorial chemical and affinity immunochemical methods to find a novel motif of unnatural peptide ligands for the fibrinogen receptor of platelets, gpIIbIIIa (αIIbβ3). The newd-amino acid motif, p(f/y)l, is unique among the ligands that bind the RGD pocket: It lacks the carboxylic acid group that is believed to coordinate with calcium in the MIDAS motif of the receptor. With an IC50of 14 μM for the most potent compound, these linear p(f/y)l peptides had affinities similar to those of linear peptides containing RGD, and reversed sequences failed to compete with binding up to 1 mM. As the new motif was so different, molecular modeling was employed to suggest a model for molecular recognition. A reversed binding mechanism common ford-amino acid mimics of naturall-amino acid peptides offers an attractive hypothesis that suggests three points of contact similar to those made by the RGD-mimicking monoclonal antibody, OPG2. Interestingly, the model proposes that π-electrons in the new motif may substitute for the carboxylate group present in all other RGD-types of ligands. Although modeling linear peptides is subjective, the π-bonding model provides intriguing possibilities for medicinal chemistry after appropriate confirmatory studies.