Synthesis and solution conformation of cyclo[RGDRGD]: a cyclic peptide with selectivity for the alpha V beta 3 receptor.
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 alpha IIb/beta 3-fibrinogen and the alpha V beta 3-vitronectin interactions and found to be selective for the alpha V beta 3 integrin. The alpha V beta 3-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 beta-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 alpha V beta 3 selectivity and solution conformation for a peptide ligand (Pfaff, M.; et al. J. Biol. Chem. 1994, 269, 20233).
Department of Chemistry, Texas A & M University, College Station 77843-3255, USA.
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D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010010:Osteoclasts / Q000187:drug effects; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects; D011487:Protein Conformation; D019030:Receptors, Vitronectin / Q000378:metabolism*; D012996:Solutions
D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; D012996:Solutions; C102044:cyclo(arginyl-glycyl-aspartyl-arginyl-glycyl-aspartyl)