title: Synthesis, SAR and in vitro evaluation of new cyclic Arg-Gly-Asp pseudopentapeptides containing a s-cis peptide bond as integrin alphavbeta3 and alphavbeta5 ligands.
abstract: 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 alphavbeta3 and alphavbeta5 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 alphavbeta3 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.
authors.affiliation: Department of Organic Chemistry Ugo Schiff University of Firenze via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Salvati
authors.forename: Franca M
authors.initials: FM
authors.lastname: Cordero
authors.forename: Federica
authors.initials: F
authors.lastname: Pisaneschi
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Melani
authors.forename: Paola
authors.initials: P
authors.lastname: Gratteri
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cini
authors.forename: Anna
authors.initials: A
authors.lastname: Bottoncetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Brandi
mesh_terms: D003198:Computer Simulation; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019030:Receptors, Vitronectin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D039302:Integrin alphaVbeta3; D016023:Integrins; D008024:Ligands; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid