Selective α4β7 Integrin Antagonists and Their Potential as Antiinflammatory Agents

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Abstract
The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin α4β7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of α4β7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that α4β7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective α4β7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded α4β7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for α4β7 by more than 500-fold to afford a potent and selective α4β1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for α4β7 compared to other integrins.