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      Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses.

      Journal of Medicinal Chemistry

      Vascular Cell Adhesion Molecule-1, Structure-Activity Relationship, Sheep, metabolism, antagonists & inhibitors, Receptors, Lymphocyte Homing, pharmacology, chemistry, chemical synthesis, Oligopeptides, Ligands, Kinetics, Jurkat Cells, Integrins, Integrin alpha4beta1, Humans, physiology, Fibronectins, Epitopes, Drug Design, Cell Line, drug effects, Cell Adhesion, toxicity, Carbachol, prevention & control, immunology, chemically induced, Bronchial Hyperreactivity, Binding Sites, Anti-Allergic Agents, Animals

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          Integrin alpha4beta1 mediates leukocyte recruitment, activation, mediator release, and apoptosis inhibition, and it plays a central role in inflammatory pathophysiology. High-affinity, selective inhibitors of alpha4beta1, based on the Leu-Asp-Val (LDV) sequence from the alternatively spliced connecting segment-1 (CS-1) peptide of cellular fibronectin, are described that employ a novel N-terminal peptide "cap" strategy. One inhibitor, BIO-1211, was approximately 10(6)-fold more potent than the starting peptide and exhibited tight-binding properties (koff = 1.4 x 10(-4) s-1, KD = 70 pM), a remarkable finding for a noncovalent, small-molecule inhibitor of a protein receptor. BIO-1211 was also 200-fold selective for the activated form of alpha4beta1, and it stimulated expression of ligand-induced epitopes on the integrin beta1 subunit, a property consistent with occupancy of the receptor's ligand-binding site. Pretreatment of allergic sheep with a 3-mg nebulized dose of BIO-1211 inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol. These results show that highly selective and potent small-molecule antagonists can be identified to integrins with primary specificity for peptide domains other than Arg-Gly-Asp (RGD); they confirm the generality of integrins as small molecule targets; and they validate alpha4beta1 as a therapeutic target for asthma.

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