title: Targeting integrins: insights into structure and activity of cyclic RGD pentapeptide mimics containing azabicycloalkane amino acids.
abstract: A small library of cyclic RGD pentapeptide mimics incorporating stereoisomeric 5,6- and 5,7-fused bicyclic lactams was synthesized. This library was found to contain high-affinity ligands for the alpha(v)beta3 integrin. The aim of this study was to investigate activity, selectivity, and structure of these ligands in order to identify new specific alpha(v)-integrin antagonists that could be evaluated as tumor angiogenesis inhibitors. In vitro screening, including receptor-binding assays to purified alpha(v)beta3, alpha(v)beta5, and alpha5beta1 integrins, and platelet aggregation assay, revealed ST1646 as a potent, highly selective alpha(v)beta3/alpha(v)beta5 integrin antagonist. Structure determination of the cyclic RGD pentapeptide mimics performed by a combination of NMR spectroscopy, and molecular mechanics and dynamics calculations showed a strong dependence of the RGD cyclopeptide conformation on lactam ring size and stereochemistry. ST1646 revealed the highest ability within the library to adopt the proper RGD orientation required for binding to the alpha(v)beta3 integrin, as deduced from the recently solved crystal structure of the extracellular segment of integrin alpha(v)beta3 in complex with a cyclic pentapeptide ligand.
authors.affiliation: Dipartimento di Chimica Organica e Industriale and Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali, (CISI), Università degli Studi di Milano, via G. Venezian 21, I-20133 Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.forename: Matteo
authors.initials: M
authors.lastname: Colombo
authors.forename: Leonardo
authors.initials: L
authors.lastname: Manzoni
authors.forename: Donatella
authors.initials: D
authors.lastname: Potenza
authors.forename: Carlo
authors.initials: C
authors.lastname: Scolastico
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Marcella
authors.initials: M
authors.lastname: Marcellini
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Pietro
authors.initials: P
authors.lastname: LoGiudice
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D006168:Guinea Pigs; D016023:Integrins / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D019096:Vitronectin / Q000378:metabolism
chemical_list: D000596:Amino Acids; D005353:Fibronectins; D016023:Integrins; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019096:Vitronectin; C047981:arginyl-glycyl-aspartic acid