Thorpe D S, Yeoman H, Chan A W, Krchnak V, Lebl M, Felder S
Department of Chemistry, Department of Discovery Biology, Selectide Corporation, a subsidiary of Hoechst Marion Roussel, 1580 E. Hanley Boulevard, Tucson, Arizona, 85737, USA.
Biochem Biophys Res Commun. 1999 Mar 24;256(3):537-41. doi: 10.1006/bbrc.1999.0374.
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 (alphaIIbbeta3). The new d-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 IC50 of 14 microM 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 for d-amino acid mimics of natural l-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 pi-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 pi-bonding model provides intriguing possibilities for medicinal chemistry after appropriate confirmatory studies.
