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Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1999 Mar 11; Vol. 42 (5), pp. 920-34. - Publication Year :
- 1999
-
Abstract
- 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.
- Subjects :
- Animals
Anti-Allergic Agents chemistry
Anti-Allergic Agents metabolism
Anti-Allergic Agents pharmacology
Binding Sites
Bronchial Hyperreactivity chemically induced
Bronchial Hyperreactivity immunology
Carbachol toxicity
Cell Adhesion drug effects
Cell Line
Drug Design
Epitopes
Fibronectins chemistry
Fibronectins physiology
Humans
Integrin alpha4beta1
Integrins metabolism
Jurkat Cells
Kinetics
Ligands
Oligopeptides chemistry
Oligopeptides metabolism
Oligopeptides pharmacology
Receptors, Lymphocyte Homing metabolism
Sheep
Structure-Activity Relationship
Vascular Cell Adhesion Molecule-1 physiology
Anti-Allergic Agents chemical synthesis
Bronchial Hyperreactivity prevention & control
Integrins antagonists & inhibitors
Oligopeptides chemical synthesis
Receptors, Lymphocyte Homing antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 42
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 10072689
- Full Text :
- https://doi.org/10.1021/jm980673g