Could Dissecting the Molecular Framework of β-Lactam Integrin Ligands Enhance Selectivity?

By dissecting the structure of beta-lactam-based ligands, a new series of compounds was designed, synthesized, and evaluated toward integrins alpha(v)beta(3), alpha(5)beta(1) and alpha(4)beta(1). New selective ligands with antagonist or agonist activities of cell adhesion in the nanomolar range were obtained. The best agonist molecules induced significant adhesion of SK-MEL-24 cells and Saos-2 cells as a valuable model for osteoblast adhesion. These data could lead to the development of new agents to improve cellular osseointegration and bone regeneration. Molecular modeling studies on prototypic compounds and alpha(v)beta(3) or alpha(5)beta(1) integrin supported the notion that ligand carboxylate fixing to the metal ion-dependent adhesion site in the beta-subunit can be sufficient for binding the receptors, while the aryl side chains play a role in determining the selectivity as well as agonism versus antagonism.