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

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 alpha(v)beta(3) and alpha(IIb)beta(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. (C) 2004 Elsevier Ltd. All rights reserved.