Abstract
N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.
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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Administration, Oral
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Aminopyridines / chemical synthesis*
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Aminopyridines / pharmacokinetics
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Aminopyridines / pharmacology
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Animals
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Cell Line
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Cell Survival / drug effects
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Crystallography, X-Ray
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Databases, Factual
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Humans
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Models, Molecular
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Molecular Conformation
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Parasitic Sensitivity Tests
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / pharmacokinetics
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Trypanocidal Agents / pharmacology
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Trypanosoma brucei brucei / drug effects
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Trypanosomiasis, African / drug therapy
Substances
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Aminopyridines
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DDD 85646
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Sulfonamides
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Trypanocidal Agents
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Acyltransferases
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glycylpeptide N-tetradecanoyltransferase
Associated data
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PDB/3H5Z
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PDB/4A2Z
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PDB/4A30
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PDB/4A31
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PDB/4A32
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PDB/4A33