Synthesis and evaluation of bivalent, peptidomimetic antagonists of the α_vβ₃ integrins

Targeting the integrin α_vβ₃ by directly interfering with its function is considered to be an effective and non-cytotoxic strategy for the treatment of tumor. In this study, a series of bivalent analogs of peptidomimetic integrin antagonists IA 1 and IAC 2 were designed, synthesized, and evaluated for their ability to inhibit the integrin α_vβ₃. All the bivalent ligands exhibited increased potency compared to that of their monomeric counterparts for the integrin α_vβ₃ with low nanomolar range binding affinity. The best bivalent ligand 6 tested in the series has an IC₅₀ = 0.09 nM evaluated by ELISA assay. We conclude that multivalency is providing a useful template for the development novel integrin α_vβ ₃ antagonists as potential therapeutics.