Novel RGD-like molecules based on the tyrosine template: Design, synthesis, and biological evaluation on isolated integrins αVβ 3/αIIbβ3 and in cellular adhesion tests

Article abstract of DOI:10.1016/j.bmc.2004.07.055

RGD (Arg-Gly-Asp) peptidomimetics have been designed for covalent anchorage on biomaterials. The tyrosine template was thus equipped with (i) a basic side chain of various flexibility, (ii) an acidic side chain, which incorporated the XPS fluorine tag, and (iii) a spacer-arm terminated by a primary amine for surface grafting. The most active compounds showed IC₅₀ values in the nanomolar range versus isolated human integrins α_Vβ ₃ and α_IIbβ₃. Preincubation of CaCo2 cells with soluble peptidomimetics (2 and 19a) prevented cellular adhesion on culture plates coated with vitronectin. On the other hand, peptidomimetics (19a and 19b) immobilized on a poly(ethylene)terephthalate membrane (PET) promoted CaCo2 cells adhesion. A modeling study at the ab initio level in MINI-1′ basis allowed to compare the various synthetic ligands of integrins and to propose novel pharmacophore structures.