Abstract
Costimulatory molecules are important regulators of T cell activation and thus favored targets for therapeutic manipulation of immune responses. One of the key costimulatory receptors is CD80, which binds the T cell ligands, CD28, and CTLA-4. We describe a set of small compounds that bind with high specificity and low nanomolar affinity to CD80. The compounds have relatively slow off-rates and block both CD28 and CTLA-4 binding, implying that they occlude the shared ligand binding site. The compounds inhibit proinflammatory cytokine release in T cell assays with submicromolar potency, and as such, they represent promising leads for the development of novel therapeutics for immune-mediated inflammatory disease. Our results also suggest that other predominantly beta proteins, such as those that dominate the cell surface, may also be accessible as potentially therapeutic targets.
MeSH terms
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Antigens, CD
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Antigens, Differentiation / drug effects
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Antigens, Differentiation / immunology
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B7-1 Antigen / drug effects*
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B7-1 Antigen / immunology
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CD28 Antigens / drug effects
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CD28 Antigens / immunology
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CTLA-4 Antigen
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Cell Line
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Cytokines / antagonists & inhibitors
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Humans
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / pharmacology*
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Immunotherapy / methods*
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Interferon-gamma / antagonists & inhibitors
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Interleukin-2 / antagonists & inhibitors
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Ligands
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Lymphocyte Activation / drug effects
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Molecular Structure
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Molecular Weight
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Protein Binding / drug effects
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Sensitivity and Specificity
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Structure-Activity Relationship
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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Time Factors
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
Substances
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Antigens, CD
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Antigens, Differentiation
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B7-1 Antigen
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CD28 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Cytokines
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Immunosuppressive Agents
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Interleukin-2
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Ligands
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Tumor Necrosis Factor-alpha
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Interferon-gamma