Novel RGD-like molecules based on the tyrosine template: design, synthesis, and biological evaluation on isolated integrins α Vβ 3/α IIbβ 3 and in cellular adhesion tests

Abstract

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 IC 50 values in the nanomolar range versus isolated human integrins α Vβ 3 and α IIbβ 3. 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.