Abstract
The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.
MeSH terms
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Allosteric Site
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Cell Adhesion / drug effects*
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Disease Models, Animal
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Drug Design
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Humans
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Integrin alpha4beta1
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Integrins / metabolism
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Intercellular Adhesion Molecule-1 / metabolism
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Lovastatin / pharmacology*
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Lymphocyte Activation / drug effects
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Lymphocyte Function-Associated Antigen-1 / chemistry
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Lymphocyte Function-Associated Antigen-1 / genetics
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Lymphocyte Function-Associated Antigen-1 / pharmacology
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Macrophage-1 Antigen / metabolism
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Mice
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Models, Molecular
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Molecular Structure
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Mutagenesis, Site-Directed
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Naphthalenes / pharmacology*
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Naphthalenes / toxicity
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Peritonitis / drug therapy
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Pravastatin / pharmacology*
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Protein Binding / drug effects
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Receptors, Lymphocyte Homing / metabolism
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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T-Lymphocytes / physiology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Integrin alpha4beta1
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Integrins
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LFA703
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Lymphocyte Function-Associated Antigen-1
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Macrophage-1 Antigen
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Naphthalenes
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Receptors, Lymphocyte Homing
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Intercellular Adhesion Molecule-1
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Lovastatin
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Pravastatin