title: Cyclic RGD-containing functionalized azabicycloalkane peptides as potent integrin antagonists for tumor targeting.
abstract: Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC(50)=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.
authors.affiliation: Istituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche, Milano, Italy. leonardo.manzoni@istm.cnr.it
authors.forename: Leonardo
authors.initials: L
authors.lastname: Manzoni
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Daniela
authors.initials: D
authors.lastname: Arosio
authors.forename: Monica
authors.initials: M
authors.lastname: Civera
authors.forename: Michael
authors.initials: M
authors.lastname: Pilkington-Miksa
authors.forename: Donatella
authors.initials: D
authors.lastname: Potenza
authors.forename: Andrea
authors.initials: A
authors.lastname: Caprini
authors.forename: Elena M V
authors.initials: EM
authors.lastname: Araldi
authors.forename: Eugenia
authors.initials: E
authors.lastname: Monferini
authors.forename: Monica
authors.initials: M
authors.lastname: Mancino
authors.forename: Francesca
authors.initials: F
authors.lastname: Podestà
authors.forename: Carlo
authors.initials: C
authors.lastname: Scolastico
mesh_terms: D000577:Amides / Q000737:chemistry; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003198:Computer Simulation; D003500:Cyclization; D003516:Cycloparaffins / Q000737:chemistry*; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012680:Sensitivity and Specificity
chemical_list: D000577:Amides; D001372:Aza Compounds; D003516:Cycloparaffins; D016023:Integrins; D008024:Ligands; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide