187735-94-0Relevant articles and documents
Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses
Lin, Ko-Chung,Ateeq, Humayun S.,Hsiung, Sherry H.,Chong, Lillian T.,Zimmerman, Craig N.,Castro, Alfredo,Lee, Wen-Cherng,Hammond, Charles E.,Kalkunte, Sandhya,Chen, Ling-Ling,Pepinsky, R. Blake,Leone, Diane R.,Sprague, Andrew G.,Abraham, William M.,Gill, Alan,Lobb, Roy R.,Adams, Steven P.
, p. 920 - 934 (2007/10/03)
Integrin α4β1 mediates leukocyte recruitment, activation, mediator release, and apoptosis inhibition, and it plays a central role in inflammatory pathophysiology. High-affinity, selective inhibitors of α4β1, 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 ~106-fold more potent than the starting peptide and exhibited tight-binding properties (k(off) = 1.4 x 10-4 s-1, K(D) = 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 α4β1, and it stimulated expression of ligand-induced epitopes on the integrin β1 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 α4β1 as a therapeutic target for asthma.
