Abstract
Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / chemistry
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Animals
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Binding Sites
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Chagas Disease / drug therapy
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / chemistry
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Humans
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Lanosterol / chemistry
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Models, Molecular
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Oxidoreductases / antagonists & inhibitors
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Oxidoreductases / chemistry
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Protein Binding
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Quinolones / chemistry*
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Sterol 14-Demethylase
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Structure-Activity Relationship
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Trypanocidal Agents / chemistry*
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Trypanosoma cruzi / enzymology*
Substances
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CYP51A1 protein, human
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Cytochrome P-450 Enzyme Inhibitors
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Quinolones
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Trypanocidal Agents
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Lanosterol
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Cytochrome P-450 Enzyme System
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Oxidoreductases
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Sterol 14-Demethylase
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Alkyl and Aryl Transferases
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p21(ras) farnesyl-protein transferase
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tipifarnib