Synthesis, SAR and in Vitro Evaluation of New Cyclic Arg-Gly-Asp Pseudopentapeptides Containing a s-cis Peptide Bond as Integrin alpha-v-beta3 and alpha-v-beta5 Ligands.

The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid (GPTM) is described. Competition binding assays to purified avb3 and avb5 integrins with respect to [125I]echistatin showed a high inhibitory activity for the (2S,7aS)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2R,7aR)-GPTM and (2S,7aS)-GPTM on the conformation of Arg-Gly-Asp sequence have been computationally investigated using as a reference the recently solved X-ray structure of cyclo(Arg-Gly-Asp-D-Phe-[N-Me]Val) in complex with the extracellular fragment of the avb3 receptor. The computational method disclosed the key role played by a bridging water molecule on differentiating the two ligands by a diverse stabilization of the ligand–protein complex.