Design and Pharmacological Characterization of α₄β₁ Integrin Cyclopeptide Agonists: Computational Investigation of Ligand Determinants for Agonism versus Antagonism

α₄β₁ integrin is a cell adhesion receptor deeply involved in the migration and accumulation of leukocytes. Therefore, integrin antagonists that inhibit leukocytes recruitment are currently regarded as a therapeutic opportunity for the treatment of inflammatory disorder, including leukocyte-related autoimmune diseases. Recently, it has been suggested that integrin agonists capable to prevent the release of adherent leukocytes might serve as therapeutic agents as well. However, very few α₄β₁ integrin agonists have been discovered so far, thus precluding the investigation of their potential therapeutic efficacy. In this perspective, we synthesized cyclopeptides containing the LDV recognition motif found in the native ligand fibronectin. This approach led to the discovery of potent agonists capable to increase the adhesion of α₄ integrin-expressing cells. Conformational and quantum mechanics computations predicted distinct ligand–receptor interactions for antagonists or agonists, plausibly referable to receptor inhibition or activation.