Shifting Towards α_Vβ₆ Integrin Ligands Using Novel Aminoproline-Based Cyclic Peptidomimetics

In recognition of the key role played by integrins in several life-threatening dysfunctions, the search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimetics with attracting α_Vβ₃ integrin affinity and selectivity, the design and straightforward synthesis of 18 new AmpRGD chemotypes bearing additional structural variants were herein implemented, to shift toward peptide-like α_Vβ₆ integrin targeted binders. The ligand competence of the synthesized products toward α_Vβ₆ was evaluated in competitive binding assays on isolated receptors, and α_Vβ₆/α_Vβ₃ selectivity was determined for a subgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.