Cyclic RGD-Containing functionalized azabicycloalkane peptides as potent integrin antagonists for tumor targeting

Cyclic RGD-contaning 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 spectro-scopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin α_vβ₃were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best α_vβ₃ integrin binder (IC₅₀ = 53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for co-valent bonding and selective homing of useful functional units.