The development of novel drugs capable to prevent cell adhesion mediated by integrins is relevant to discover novel drug targets in the field of allergy/inflammation and cancer. We are interested in in vitro and in vivo assays with the aim to characterize novel integrin antagonists. Levocabastine is an antiallergic drug acting as a histamine H1-receptor antagonist, employed for the topical treatment of allergic conjunctivitis (AC). In allergic conjunctivitis, it may also antagonize up-regulation of the intercellular adhesion molecule-1 (ICAM-1) expressed on epithelial conjunctival cells. However, little is known about its effects on eosinophils, important effector cells in AC. Increased levels of cell adhesion molecules on the microvasculature and factors that regulate them are likely to be responsible for the conjunctival infiltration of circulating cells and may perpetuate inflammation in AC. The central mechanism in the pathogenesis of this disease is IgE-mediated mast cell degranulation and infiltration and activation of T lymphocytes, basophils, eosinophils, and other cells in the conjunctiva, with the involvement of conjunctival epithelial cells. Its severity correlates with the degree of eosinophil infiltration into the conjunctiva, which is mediated by chemokines that stimulate the production of adhesion molecules like ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) on the endothelial cell surface. The mechanisms regulating eosinophil adhesion to the ocular surface during allergic inflammation are still largely unknown.

We have provided evidence that in a scintillation proximity assay levocabastine displaced ¹²⁵I-FN binding to human integrin a4b1 and, in flow cytometry analysis and antagonized the binding of a primary antibody to integrin a4 expressed on the Jurkat cell surface. Levocabastine, but not chlorpheniramine, binds the a4b1 integrin and prevents eosinophil adhesion to VCAM-I, FN or human umbilical vascular endothelial cells (HUVEC) in vitro. Similarly, levocabastine affects aLb2/ICAM-I-mediated adhesion of Jurkat cells. In a model of AC levocabastine eye drops reduced the clinical aspects of the late-phase reaction and the conjunctival expression of a4b1 integrin by reducing infiltrated eosinophils. We propose that blockade of integrin-mediated cell adhesion might be a target of the antiallergic action of levocabastine and may play a role in preventing eosinophil adhesion and infiltration in allegic conjunctivitis.

The synthesis and the antiadhesion activity of libraries of peptidomimetics capable to recognize avb3 and a5b1 integrins and acting as inhibitors of fibronectin adhesion to SK-MEL-24 and K562 cells is investigated. To evaluate the potential activity as avb3 and a5b1 integrin inhibitors, we test their ability to inhibit the adhesion of an several cell lines to a specific substrate.