Combinatorial chemistry reveals a new motif that binds the platelet fibrinogen receptor, gpIIbIIIa

Among cell adhesion molecules, the classic Arg-Gly-Asp (RGD) motif is the b est studied. We used combinatorial chemical and affinity immunochemical met hods to find a novel motif of unnatural peptide ligands for the fibrinogen receptor of platelets, gpIIbIIIa (alpha(IIb)beta(3)). The new D-amino acid motif, p(f/y)l, is unique among the ligands that bind the RGD pocket: It la cks the carboxylic acid group that is believed to coordinate with calcium i n the MIDAS motif of the receptor. With an IC50 of 14 mu M for the most pot ent compound, these linear p(f/y)l peptides had affinities similar to those of linear peptides containing RGD, and reversed sequences failed to compet e with binding up to 1 mM. As the new motif was so different, molecular mod eling was employed to suggest a model for molecular recognition, A reversed binding mechanism common for D amino acid mimics of natural L-amino acid p eptides offers an attractive hypothesis that suggests three points of conta ct similar to those made by the RGD-mimicking monoclonal antibody, OPG2. In terestingly, the model proposes that pi-electrons in the new motif may subs titute for the carboxylate group present in all other RGD-types of ligands. Although modeling linear peptides is subjective, the pi-bonding model prov ides intriguing possibilities for medicinal chemistry after appropriate con firmatory studies. (C) 1999 Academic Press.