Publication Date:
2010-04-03
Description:
African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917743/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917743/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frearson, Julie A -- Brand, Stephen -- McElroy, Stuart P -- Cleghorn, Laura A T -- Smid, Ondrej -- Stojanovski, Laste -- Price, Helen P -- Guther, M Lucia S -- Torrie, Leah S -- Robinson, David A -- Hallyburton, Irene -- Mpamhanga, Chidochangu P -- Brannigan, James A -- Wilkinson, Anthony J -- Hodgkinson, Michael -- Hui, Raymond -- Qiu, Wei -- Raimi, Olawale G -- van Aalten, Daan M F -- Brenk, Ruth -- Gilbert, Ian H -- Read, Kevin D -- Fairlamb, Alan H -- Ferguson, Michael A J -- Smith, Deborah F -- Wyatt, Paul G -- 077503/Wellcome Trust/United Kingdom -- 077705/Wellcome Trust/United Kingdom -- 085622/Wellcome Trust/United Kingdom -- 087590/Wellcome Trust/United Kingdom -- 1097737/Canadian Institutes of Health Research/Canada -- G0900138/Medical Research Council/United Kingdom -- G0900138(90614)/Medical Research Council/United Kingdom -- WT077503/Wellcome Trust/United Kingdom -- WT077705/Wellcome Trust/United Kingdom -- WT083481,/Wellcome Trust/United Kingdom -- WT085622/Wellcome Trust/United Kingdom -- England -- Nature. 2010 Apr 1;464(7289):728-32. doi: 10.1038/nature08893.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360736" target="_blank"〉PubMed〈/a〉
Keywords:
Acyltransferases/*antagonists & inhibitors/metabolism
;
Aminopyridines/chemistry/metabolism/pharmacology/therapeutic use
;
Animals
;
Antiparasitic Agents/chemistry/metabolism/*pharmacology/*therapeutic use
;
Enzyme Assays
;
Enzyme Inhibitors/chemistry/metabolism/pharmacology/therapeutic use
;
Female
;
Humans
;
Mice
;
Molecular Structure
;
Pyrazoles/chemistry/metabolism/pharmacology/therapeutic use
;
Rats
;
Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use
;
Time Factors
;
Trypanosoma brucei brucei/*drug effects/*enzymology/growth & development
;
Trypanosomiasis, African/*drug therapy/*parasitology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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