Cyclic RGD-containing functionalized azabicycloalkane peptides as potent integrin antagonists for tumor targeting.
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.
Manzoni
Leonardo
L
Istituto di Scienze e Tecnologie Molecolari, Consiglio Nazionale delle Ricerche, Milano, Italy. leonardo.manzoni@istm.cnr.it
Belvisi
Laura
L
Arosio
Daniela
D
Civera
Monica
M
Pilkington-Miksa
Michael
M
Potenza
Donatella
D
Caprini
Andrea
A
Araldi
Elena M V
EM
Monferini
Eugenia
E
Mancino
Monica
M
Podestà
Francesca
F
Scolastico
Carlo
C
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
D000577:Amides; D001372:Aza Compounds; D003516:Cycloparaffins; D016023:Integrins; D008024:Ligands; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide