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

By dissecting the structure of β-lactam-based ligands, a new series of compounds was designed, synthesized, and evaluated toward integrins α_vβ₃, α₅β₁, and α₄β₁. 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 α_vβ₃ or α₅β₁ Integrin supported the notion that ligand carboxylate fixing to the metal ion-dependent adhesion site in the β-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.