Targeting integrins: Insights into structure and activity of cyclic RGD pentapeptide mimics containing azabicycloalkane amino acids Original Research Article

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 αvβ3 integrin. The aim of this study was to investigate activity, selectivity, and structure of these ligands in order to identify new specific αv-integrin antagonists that could be evaluated as tumor angiogenesis inhibitors. In vitro screening, including receptor-binding assays to purified αvβ3, αvβ5, and α5β1 integrins, and platelet aggregation assay, revealed ST1646 as a potent, highly selective αvβ3/αvβ5 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 αvβ3 integrin, as deduced from the recently solved crystal structure of the extracellular segment of integrin αvβ3 in complex with a cyclic pentapeptide ligand.