Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses

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