Peptidomimetic probes for modulating α4β1 integrin activity

The accumulation of leukocytes in various organs contributes to the pathogenesis of a number of human autoimmune diseases such as asthma, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, hepatitis C, and multiple sclerosis.[1] The inflammatory processes leading to tissue damage and disease are mediated in part by the α4β1 integrins expressed on the leukocyte cell surface. These glycoprotein receptors modulate cell adhesion via interaction with their primary ligands VCAM e MAdCAM, expressed in the affected tissue. Binding results in firm adhesion of the leukocytes to the vessel wall followed by entry into the affected tissue.[2] Elevated CAM expression in various organs has been linked with several autoimmune diseases. In addition, increasing evidence points to important causative links between inflammation and cancer, infact the α4β1 integrin is also involved in the formation of new cancer blood vessels.[3] Integrin antagonists capable of inhibiting the adhesion of leucocytes to their ligands might therefore represent a new approach for treatment of human inflammatory diseases and cancer. In this work we discuss a library of peptidomimetic inhibitors of α4β1 integrin based on a rigid central scaffold, β-amino acid residues, and partially modified retro-inverso sequence. The inhibitory activity has been assessed by adhesion experiments of Jurkat E6.1 cells to VCAM-1 and fibronectin, by Scintillation Proximity Assay (SPA), that determines the binding affinity of the compound to the integrin, by flow cytometry, that provides insight into the ability of ligands to induce conformational changes of integrin α4β1, and by model of ocular inflammation in vivo, that allows to study the effect of α4β1 antagonists on signaling pathways leading to activation of NF-kB, VEGF and TNF-α in the context of adhesion of immune cells and vascular leakage