Shifting Towards alpha(V)beta(6)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 alpha(V)beta(3)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 alpha(V)beta(6)integrin targeted binders. The ligand competence of the synthesized products toward alpha(V)beta(6)was evaluated in competitive binding assays on isolated receptors, and alpha(V)beta(6)/alpha(V)beta(3)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.