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

Two c[RGDfX] cyclopeptides, having either l- or d-morpholine-3-COOH (Mor) as the X amino acid were developed as ligands for αvβ3/αvβ5 integrins. Biological assays showed only d-Mor-containing cyclopentapeptide capable to bind αvβ3 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 αvβ3 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.