N-myristoyltransferase inhibitors as new leads to treat sleeping sickness View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-04

AUTHORS

Julie A. Frearson, Stephen Brand, Stuart P. McElroy, Laura A. T. Cleghorn, Ondrej Smid, Laste Stojanovski, Helen P. Price, M. Lucia S. Guther, Leah S. Torrie, David A. Robinson, Irene Hallyburton, Chidochangu P. Mpamhanga, James A. Brannigan, Anthony J. Wilkinson, Michael Hodgkinson, Raymond Hui, Wei Qiu, Olawale G. Raimi, Daan M. F. van Aalten, Ruth Brenk, Ian H. Gilbert, Kevin D. Read, Alan H. Fairlamb, Michael A. J. Ferguson, Deborah F. Smith, Paul G. Wyatt

ABSTRACT

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. More... »

PAGES

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Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature08893

DOI

http://dx.doi.org/10.1038/nature08893

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1018515085

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20360736


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