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

Ko Chung Lin, Humayun S. Ateeq, Sherry H. Hsiung, Lillian T. Chong, Craig N. Zimmerman, Alfredo Castro, Wen Cherng Lee, Charles E. Hammond, Sandhya Kalkunte, Ling Ling Chen, R. Blake Pepinsky, Diane R. Leone, Andrew G. Sprague, William M. Abraham, Alan Gill, Roy R. Lobb, Steven P. Adams

Research output: Contribution to journalArticlepeer-review

202 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)920-934
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number5
StatePublished - Mar 11 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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