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Synthesis and Solution Conformation of Cyclo[RGDRGD]:  A Cyclic Peptide with Selectivity for the αVβ3 Receptor

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journal contribution
posted on 25.10.1996, 00:00 by Kevin Burgess, Dongyeol Lim, Shaker A. Mousa
Three peptides, cyclo[RGDRGD], cyclo[RGDRGd] (d = d-Asp), and the linear sequence RGDRGD, were prepared via solid phase syntheses. These were tested in binding assays based upon the αIIb/β3-fibrinogen and the αVβ3-vitronectin interactions and found to be selective for the αVβ3 integrin. The αVβ3-vitronectin is important in bone regeneration, hence the compounds were also tested in an osteoclast regeneration assay; all three compounds, cyclo[RGDRGD], cyclo[RGDRGd], and RGDRGD, showed modest activities. Molecular modeling, NMR, and CD studies were undertaken to elucidate the conformational preferences of cyclo[RGDRGD] in aqueous solutions. Results from these studies strongly suggest that the molecule tends to adopt a type I β-turn conformation with a relatively short distance between the Asp and Arg side chains. These observations are in harmony with the first correlations made between αVβ3 selectivity and solution conformation for a peptide ligand (Pfaff, M.; et al. J. Biol. Chem. 1994, 269, 20233).