Shifting Towards αVβ6 Integrin Ligands Using Novel Aminoproline-Based Cyclic Peptidomimetics

In recognition of the key role exerted 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 alphaVbeta3 integrin affinity and selectivity, the design and straightforward synthesis of eighteen new AmpRGD chemotypes bearing additional structural variants were herein implemented, to shift toward peptide-like alphaVbeta6 integrin targeted binders. Hence, the ligand competence of the synthesized products toward alphaVbeta6 was evaluated in competitive binding assays on isolated receptors, and alphaVbeta6/alphaVbeta3 selectivity 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.