Shifting Towards αV β6 Integrin Ligands Using Novel Aminoproline-Based Cyclic Peptidomimetics

Abstract

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_V β₃ 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_V β₆ integrin targeted binders. The ligand competence of the synthesized products toward α_V β₆ was evaluated in competitive binding assays on isolated receptors, and α_V β₆ /α_V β₃ 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.

Keywords: RGD peptides; integrins; ligand design; peptidomimetics; structure-activity relationships.