Novel RGD-like molecules based on the tyrosine template: design, synthesis, and biological evaluation on isolated integrins alphaVbeta3/alphaIIbbeta3 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 alphaVbeta3 and alphaIIbbeta3. 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.
Biltresse
Stephane
S
Unité de Chimie Organique et Médicinale, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur, 1, B-1348 Louvain-la-Neuve, Belgium.
Attolini
Mireille
M
Dive
Georges
G
Cordi
Alex
A
Tucker
Gordon C
GC
Marchand-Brynaert
Jacqueline
J
D040761:Biomimetic Materials; D002448:Cell Adhesion / Q000187:drug effects*; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry*
D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; C047981:arginyl-glycyl-aspartic acid