Abstract

The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1 H-pyrrolizine-7a(5 H)-carboxylic acid (GPTM) is described. Competition binding assays to purified α vβ 3 and α vβ 5 integrins with respect to [ 125I]echistatin showed a high inhibitory activity for the (2 S,7a S)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2 R,7a R)-GPTM and (2 S,7a S)-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 α vβ 3 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.

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