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

Lin, K C ; Ateeq, H S ; Hsiung, S H ; Chong, L T ; Zimmerman, C N ; Castro, A ; Lee, W C ; Hammond, C E ; Kalkunte, S ; Chen, L L ; Pepinsky, R B ; Leone, D R ; Sprague, A G ; Abraham, W M ; Gill, A ; Lobb, R R ; Adams, S P

Journal of medicinal chemistry, 11 March 1999, Vol.42(5), pp.920-34 [Peer Reviewed Journal]

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  • Title:
    Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses
  • Author: Lin, K C ; Ateeq, H S ; Hsiung, S H ; Chong, L T ; Zimmerman, C N ; Castro, A ; Lee, W C ; Hammond, C E ; Kalkunte, S ; Chen, L L ; Pepinsky, R B ; Leone, D R ; Sprague, A G ; Abraham, W M ; Gill, A ; Lobb, R R ; Adams, S P
  • Description: 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.
  • Is Part Of: Journal of medicinal chemistry, 11 March 1999, Vol.42(5), pp.920-34
  • Identifier: ISSN: 0022-2623 ; PMID: 10072689 Version:1
  • Subjects: Anti-Allergic Agents -- Chemical Synthesis ; Bronchial Hyperreactivity -- Prevention & Control ; Integrins -- Antagonists & Inhibitors ; Oligopeptides -- Chemical Synthesis ; Receptors, Lymphocyte Homing -- Antagonists & Inhibitors
  • Language: English

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