期刊
NATURE
卷 464, 期 7289, 页码 728-U100出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08893
关键词
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资金
- Wellcome Trust [WT077705, WT083481, WT077503, WT085622]
- Scottish Funding Council [HR04013]
- Translational Biology Theme of SULSA
- European Regional Development Fund
- Wolfson Foundation
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation and Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation, Merck
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
- MRC [G0900138] Funding Source: UKRI
- Medical Research Council [G0900138] Funding Source: researchfish
African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for similar to 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.
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