Abstract
N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases / antagonists & inhibitors*
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Acyltransferases / metabolism
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Antifungal Agents / chemical synthesis
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Antifungal Agents / chemistry
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Antifungal Agents / pharmacology*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Leishmania / drug effects
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Leishmania / enzymology*
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Models, Molecular
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Molecular Structure
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Parasitic Sensitivity Tests
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Peptidomimetics / chemical synthesis
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Peptidomimetics / chemistry
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Peptidomimetics / pharmacology*
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Plasmodium / drug effects
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Plasmodium / enzymology*
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Structure-Activity Relationship
Substances
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Antifungal Agents
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Enzyme Inhibitors
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Peptidomimetics
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Acyltransferases
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glycylpeptide N-tetradecanoyltransferase