Synthesis, SAR and in vitro evaluation of new cyclic Arg-Gly-Asp pseudopentapeptides containing a s- cis peptide bond as integrin α vβ 3 and α vβ 5 ligands

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 8; pp. 4262 - 4271
• Main Authors: Salvati, Maria, Cordero, Franca M., Pisaneschi, Federica, Melani, Fabrizio, Gratteri, Paola, Cini, Nicoletta, Bottoncetti, Anna, Brandi, Alberto
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 2008
• Subjects: Hydrogen bonds; Molecular dynamics; Nitrogen heterocycles; RGD; All; DIPEA; TBTU; Molecular dynamics; TFA; RGD; NMM; Hydrogen bonds; Nitrogen heterocycles; Pbf; DMAP; HOBt; Fmoc; DMF; DIC
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.02.080

MD simulation of new Arg-Gly-Asp ligand/α vβ 3 complexes showed the key role played by a bridging water molecule in the ligand–protein interaction. 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.