Morpholine-based RGD-cyclopentapeptides as αvβ3/αvβ5 integrin ligands: Role of configuration towards receptor binding affinity

Abstract Two c [RGDfX] cyclopeptides, having either l - or d -morpholine-3-COOH (Mor) as the X amino acid were developed as ligands for α v β 3 /α v β 5 integrins. Biological assays showed only d -Mor-containing cyclopentapeptide capable to bind α v β 3 integrin with a low nanomolar affinity according to a two-site model, thus revealing a connection between the configuration of Mor and the preferred binding to α v β 3 integrin. Conformational analysis showed different structural preferences for the two peptides induced by the two enantiomeric cyclic amino acids, suggesting a role of the stereochemistry of Mor on the overall peptide conformation and on the presentation of the pharmacophoric Arg and Asp side chains.