Synthesis and evaluation of bivalent, peptidomimetic antagonists of the αvβ3 integrins

Targeting the integrin αvβ3 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 αvβ3. All the bivalent ligands exhibited increased potency compared to that of their monomeric counterparts for the integrin αvβ3 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 αvβ3 antagonists as potential therapeutics.

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