N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

被引:241
作者
Frearson, Julie A. [1 ]
Brand, Stephen [1 ]
McElroy, Stuart P. [1 ]
Cleghorn, Laura A. T. [1 ]
Smid, Ondrej [1 ]
Stojanovski, Laste [1 ]
Price, Helen P. [3 ,5 ]
Guther, M. Lucia S. [1 ]
Torrie, Leah S. [1 ]
Robinson, David A. [1 ]
Hallyburton, Irene [1 ]
Mpamhanga, Chidochangu P. [1 ]
Brannigan, James A. [4 ]
Wilkinson, Anthony J. [4 ]
Hodgkinson, Michael [3 ,5 ]
Hui, Raymond [6 ]
Qiu, Wei [6 ]
Raimi, Olawale G. [2 ]
van Aalten, Daan M. F. [2 ]
Brenk, Ruth [1 ]
Gilbert, Ian H. [1 ]
Read, Kevin D. [1 ]
Fairlamb, Alan H. [1 ]
Ferguson, Michael A. J. [1 ]
Smith, Deborah F. [3 ,5 ]
Wyatt, Paul G. [1 ]
机构
[1] Univ Dundee, Div Biol Chem & Drug Discovery, Drug Discovery Unit, Coll Life Sci, Dundee DD1 5EH, Scotland
[2] Univ Dundee, Div Mol Microbiol, Coll Life Sci, Dundee DD1 5EH, Scotland
[3] Univ York, Dept Biol, Ctr Immunol & Infect, York YO10 5YW, N Yorkshire, England
[4] Univ York, Dept Chem, Struct Biol Lab, York YO10 5YW, N Yorkshire, England
[5] Univ York, Hull York Med Sch, York YO10 5YW, N Yorkshire, England
[6] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada
基金
英国惠康基金;
关键词
VARIANT SURFACE GLYCOPROTEIN; TRYPANOSOMA-BRUCEI; AFRICAN TRYPANOSOMES; MYRISTOYL-COA; DRUG TARGET; SUBSTRATE PROTEINS; ENDOCYTOSIS; LEISHMANIA; TRAFFICKING; COMPLEXES;
D O I
10.1038/nature08893
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:728 / U100
页数:7
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