N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

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 and Paul G. Wyatt ()
Additional contact information
Julie A. Frearson: Drug Discovery Unit
Stephen Brand: Drug Discovery Unit
Stuart P. McElroy: Drug Discovery Unit
Laura A. T. Cleghorn: Drug Discovery Unit
Ondrej Smid: Drug Discovery Unit
Laste Stojanovski: Drug Discovery Unit
Helen P. Price: Centre for Immunology and Infection, University of York, Heslington, York YO10 5YW, UK
M. Lucia S. Guther: Drug Discovery Unit
Leah S. Torrie: Drug Discovery Unit
David A. Robinson: Drug Discovery Unit
Irene Hallyburton: Drug Discovery Unit
Chidochangu P. Mpamhanga: Drug Discovery Unit
James A. Brannigan: Structural Biology Laboratory
Anthony J. Wilkinson: Structural Biology Laboratory
Michael Hodgkinson: Centre for Immunology and Infection, University of York, Heslington, York YO10 5YW, UK
Raymond Hui: Structural Genomics Consortium, University of Toronto, MaRS South Tower, 7th Floor, 101 College Street, Toronto, Ontario M5G 1L7, Canada
Wei Qiu: Structural Genomics Consortium, University of Toronto, MaRS South Tower, 7th Floor, 101 College Street, Toronto, Ontario M5G 1L7, Canada
Olawale G. Raimi: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Daan M. F. van Aalten: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
Ruth Brenk: Drug Discovery Unit
Ian H. Gilbert: Drug Discovery Unit
Kevin D. Read: Drug Discovery Unit
Alan H. Fairlamb: Drug Discovery Unit
Michael A. J. Ferguson: Drug Discovery Unit
Deborah F. Smith: Centre for Immunology and Infection, University of York, Heslington, York YO10 5YW, UK
Paul G. Wyatt: Drug Discovery Unit

Nature, 2010, vol. 464, issue 7289, 728-732

Abstract: Abstract African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for ∼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.

Date: 2010
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/nature08893 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:464:y:2010:i:7289:d:10.1038_nature08893

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/nature08893

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().