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

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2006, Vol.14 (1), p.169-180
Main Authors: BELVISI, Laura, BERNARDI, Anna, LOGIUDICE, Pietro, PISANO, Claudio, COLOMBO, Matteo, MANZONI, Leonardo, POTENZA, Donatella, SCOLASTICO, Carlo, GIANNINI, Giuseppe, MARCELLINI, Marcella, RICCIONI, Teresa, CASTORINA, Massimo
Format: Article
Language:English
Subjects:
Amino Acids - chemistry
Animals
Antineoplastic agents
Biological and medical sciences
Cell Adhesion - drug effects
Fibronectins - metabolism
General aspects
Guinea Pigs
Integrins - drug effects
Integrins - metabolism
Magnetic Resonance Spectroscopy
Medical sciences
Oligopeptides - chemistry
Oligopeptides - pharmacology
Pharmacology. Drug treatments
Platelet Aggregation Inhibitors - chemistry
Platelet Aggregation Inhibitors - pharmacology
Protein Conformation
Structure-Activity Relationship
Vitronectin - metabolism
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2005.08.048