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From the same journal

From the same journal

N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

Research output: Contribution to journalArticle

Author(s)

  • Julie A. Frearson
  • Stephen Brand
  • Stuart P. McElroy
  • Laura A. T. Cleghorn
  • Ondrej Smid
  • Laste Stojanovski
  • M. Lucia S. Guther
  • Leah S. Torrie
  • David A. Robinson
  • Irene Hallyburton
  • Chidochangu P. Mpamhanga
  • 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
  • Paul G. Wyatt

Department/unit(s)

Publication details

JournalNature
DatePublished - 1 Apr 2010
Issue number7289
Volume464
Number of pages5
Pages (from-to)728-732
Original languageEnglish

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.

    Research areas

  • VARIANT SURFACE GLYCOPROTEIN, TRYPANOSOMA-BRUCEI, AFRICAN TRYPANOSOMES, MYRISTOYL-COA, DRUG TARGET, SUBSTRATE PROTEINS, ENDOCYTOSIS, LEISHMANIA, TRAFFICKING, COMPLEXES

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