Post-translational import of protein into the endoplasmic reticulum of a trypanosome: An in vitro system for discovery of anti-trypanosomal chemical entities

Bhargavi Patham, Josh Duffy, Ariel Lane, Richard C. Davis, Peter Wipf, Sheara W. Fewell, Jeffrey L. Brodsky, Kojo Mensa-Wilmot

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

HAT (human African trypanosomiasis), caused by the protozoan parasite Trypanosoma brucei, is an emerging disease for which new drugs are needed. Expression of plasma membrane proteins [e.g. VSG (variant surface glycoprotein)] is crucial for the establishment and maintenance of an infection by T. brucei. Transport of a majority of proteins to the plasma membrane involves their translocation into the ER (endoplasmic reticulum). Thus inhibition of protein import into the ER of T. brucei would be a logical target for discovery of lead compounds against trypanosomes. We have developed a TbRM (T. brucei microsome) system that imports VSG_117 post-translationally. Using this system, MAL3-101, equisetin and CJ-21,058 were discovered to be small molecule inhibitors of VSG_117 translocation into the ER. These agents also killed bloodstream T. brucei in vitro; the concentrations at which 50% of parasites were killed (IC50) were 1.5 μM (MAL3-101), 3.3 μM (equisetin) and 7 μM (CJ-21,058). Thus VSG_117 import into TbRMs is a rapid and novel assay to identify 'new chemical entities' (e.g. MAL3-101, equisetin and CJ-21,058) for anti-trypanosome drug development.

Original languageEnglish (US)
Pages (from-to)507-517
Number of pages11
JournalBiochemical Journal
Volume419
Issue number2
DOIs
StatePublished - Apr 15 2009

Keywords

  • Drug development
  • Endoplasmic reticulum (ER)
  • Microsome
  • Protein import
  • Trypanosoma brucei

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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