Abstract
Bz-423 is a 1,4-benzodiazepine that suppresses disease in lupus-prone mice by selectively killing pathogenic lymphocytes, and it is less toxic compared to current lupus drugs. Cells exposed to Bz-423 rapidly generate O(2)(-) within mitochondria, and this reactive oxygen species is the signal initiating apoptosis. Phage display screening revealed that Bz-423 binds to the oligomycin sensitivity conferring protein (OSCP) component of the mitochondrial F(1)F(0)-ATPase. Bz-423 inhibited the F(1)F(0)-ATPase in vitro, and reconstitution experiments demonstrated that inhibition was mediated by the OSCP. This target was further validated by generating cells with reduced OSCP expression using RNA interference and studying the sensitivity of these cells to Bz-423. Our findings help explain the efficacy and selectivity of Bz-423 for autoimmune lymphocytes and highlight the OSCP as a target to guide the development of novel lupus therapeutics.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphatases / antagonists & inhibitors
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Adenosine Triphosphatases / metabolism
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Animals
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Benzodiazepines / pharmacology*
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / metabolism
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Cattle
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Cell Death / drug effects
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Cell Line
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Cloning, Molecular
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / pharmacology*
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Humans
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Immunologic Factors / pharmacology*
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Indicators and Reagents
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Lupus Erythematosus, Systemic / drug therapy
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / metabolism
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Mitochondria / drug effects
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Mitochondria / enzymology*
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Mitochondria, Heart / drug effects
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Mitochondria, Heart / enzymology
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Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors*
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Oxygen Consumption / drug effects
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RNA, Small Interfering / pharmacology
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Transfection
Substances
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Carrier Proteins
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Enzyme Inhibitors
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Immunologic Factors
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Indicators and Reagents
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Membrane Proteins
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RNA, Small Interfering
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Benzodiazepines
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Adenosine Triphosphatases
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F1F0-ATP synthase
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Mitochondrial Proton-Translocating ATPases
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oligomycin sensitivity-conferring protein
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Bz-423