Abstract
HIV-1 viral protein R (Vpr) is one of the human immunodeficiency virus type 1 encoded proteins that have important roles in viral pathogenesis. However, no clinical drug for AIDS therapy that targets Vpr has been developed. Here, we have established a screening system to isolate Vpr inhibitors using budding yeast cells. We purified a Vpr inhibitory compound from fungal metabolites and identified it as fumagillin, a chemical already known to be a potent inhibitor of angiogenesis. Fumagillin not only reversed the growth inhibitory activity of Vpr in yeast and human cells, but also inhibited Vpr-dependent viral gene expression upon the infection of human macrophages.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopeptidases / metabolism
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Cell Cycle / drug effects
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Cell Line
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Cell Proliferation
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Cyclohexanes
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Drug Evaluation, Preclinical
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Fatty Acids, Unsaturated / chemistry
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Fatty Acids, Unsaturated / pharmacology*
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Gene Expression Regulation, Viral / drug effects
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Gene Products, vpr / antagonists & inhibitors*
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Gene Products, vpr / metabolism
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HIV-1 / drug effects*
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HIV-1 / physiology*
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Humans
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Macrophages / drug effects*
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Macrophages / virology*
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Metalloendopeptidases / metabolism
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Molecular Structure
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Saccharomyces cerevisiae / cytology
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Saccharomyces cerevisiae / drug effects
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Sesquiterpenes
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Signal Transduction / drug effects
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vpr Gene Products, Human Immunodeficiency Virus
Substances
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Cyclohexanes
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Fatty Acids, Unsaturated
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Gene Products, vpr
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Sesquiterpenes
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vpr Gene Products, Human Immunodeficiency Virus
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fumagillin
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Aminopeptidases
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methionine aminopeptidase 2
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Metalloendopeptidases