Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 18, Pages 8374-8389Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00884
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Funding
- Wellcome Trust [WT077705, WT094090, WT083481]
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Crystallography has guided the hybridization of two series of Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect of combining the selectivity enhancing elements from two pharmacophores is shown to be additive and has led to compounds that have greater than 1000-fold selectivity for TbNMT vs HsNMT. Further optimization of the hybrid series has identified compounds with significant trypanocidal activity capable of crossing the blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able to demonstrate full cures in vivo in a mouse model of stage 2 African sleeping sickness. This and previous work provides very strong validation for NMT as a drug target for human African trypanosomiasis in both the peripheral and central nervous system stages of disease.
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