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

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.

• Authors: K c Lin, H S Ateeq, S H Hsiung, L T Chong, C N Zimmerman, A Castro, W C Lee, C E Hammond, S Kalkunte, L L Chen, R B Pepinsky, D R Leone, A G Sprague, W M Abraham, A Gill, R R Lobb, S P Adams
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 42 Issue 5 Pg. 920-34 (Mar 11 1999) ISSN: 0022-2623 [Print] United States
• PMID: 10072689 (Publication Type: Journal Article)

Chemical References

• Anti-Allergic Agents
• Epitopes
• Fibronectins
• Integrin alpha4beta1
• Integrins
• Ligands
• Oligopeptides
• Receptors, Lymphocyte Homing
• Vascular Cell Adhesion Molecule-1
• leucyl-aspartyl-valine
• BIO 1211
• Carbachol

Topics

• Animals
• Anti-Allergic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
• Binding Sites
• Bronchial Hyperreactivity (chemically induced, immunology, prevention & control)
• Carbachol (toxicity)
• Cell Adhesion (drug effects)
• Cell Line
• Drug Design
• Epitopes
• Fibronectins (chemistry, physiology)
• Humans
• Integrin alpha4beta1
• Integrins (antagonists & inhibitors, metabolism)
• Jurkat Cells
• Kinetics
• Ligands
• Oligopeptides (chemical synthesis, chemistry, metabolism, pharmacology)
• Receptors, Lymphocyte Homing (antagonists & inhibitors, metabolism)
• Sheep
• Structure-Activity Relationship
• Vascular Cell Adhesion Molecule-1 (physiology)