Projects per year
Abstract
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.
Original language | English |
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Pages (from-to) | 728-732 |
Number of pages | 7 |
Journal | Nature |
Volume | 464 |
Issue number | 7289 |
DOIs | |
Publication status | Published - 1 Apr 2010 |
Keywords
- VARIANT SURFACE GLYCOPROTEIN
- TRYPANOSOMA-BRUCEI
- AFRICAN TRYPANOSOMES
- MYRISTOYL-COA
- DRUG TARGET
- SUBSTRATE PROTEINS
- ENDOCYTOSIS
- LEISHMANIA
- TRAFFICKING
- COMPLEXES
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Dive into the research topics of 'N-myristoyltransferase inhibitors as new leads to treat sleeping sickness'. Together they form a unique fingerprint.Projects
- 3 Finished
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Aref#d: 21559. Molecular Mechanisms of Fungal Cell Wall Assembly (Programme Grant)
van Aalten, D. (Investigator)
1/11/09 → 31/10/14
Project: Research
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Aref#d: 21318. Molecular Mechanisms of O-GlcNAc Signalling (Senior Fellowship Renewal)
van Aalten, D. (Investigator)
1/06/09 → 29/02/16
Project: Research
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Aref#d: 20731. The Biosynthesis of Glycoproteins in Trypanosoma Brucei: Basic and Translational Research
Ferguson, M. (Investigator) & Gilbert, I. (Investigator)
1/10/08 → 31/05/14
Project: Research
Press/Media
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Drug breakthrough in fight against neglected diseases
Wyatt, P., Fairlamb, A. H. & Ferguson, M. A. J.
1/04/10
1 item of Media coverage
Press/Media: Research