eprintid: 18942
rev_number: 28
userid: 1419
dir: disk0/00/01/89/42
datestamp: 2013-06-12 20:29:18
lastmod: 2021-06-12 22:55:50
status_changed: 2013-06-12 20:29:18
type: article
metadata_visibility: show
item_issues_count: 0
eprint_status: archive
creators_name: Patham, B
creators_name: Duffy, J
creators_name: Lane, A
creators_name: Davis, RC
creators_name: Wipf, P
creators_name: Fewell, SW
creators_name: Brodsky, JL
creators_name: Mensa-Wilmot, K
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creators_email: pwipf@pitt.edu
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creators_email: jbrodsky@pitt.edu
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creators_id: PWIPF
creators_id: 
creators_id: JBRODSKY
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creators_orcid: 0000-0002-6984-8486
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title: Post-translational import of protein into the endoplasmic reticulum of a trypanosome: An in vitro system for discovery of anti-trypanosomal chemical entities
ispublished: pub
divisions: sch_as_chemistry
full_text_status: public
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. © The Authors Journal compilation.
date: 2009-04-15
date_type: published
publication: Biochemical Journal
volume: 419
number: 2
pagerange: 507 - 517
refereed: TRUE
issn: 0264-6021
id_number: 10.1042/BJ20081787
other_id: NLM NIHMS140541
other_id: NLM PMC2769561
pmcid: PMC2769561
pmid: 19196237
mesh_headings: Animals
mesh_headings: Endoplasmic Reticulum--metabolism
mesh_headings: HeLa Cells
mesh_headings: Humans
mesh_headings: Naphthalenes--pharmacology
mesh_headings: Protein Transport--drug effects
mesh_headings: Pyrrolidinones--pharmacology
mesh_headings: Rats
mesh_headings: Tetrahydronaphthalenes--pharmacology
mesh_headings: Trypanosoma brucei brucei--metabolism
mesh_headings: Variant Surface Glycoproteins, Trypanosoma--genetics
mesh_headings: Variant Surface Glycoproteins, Trypanosoma--metabolism
chemical_names: CJ 21058
chemical_names: Naphthalenes
chemical_names: Pyrrolidinones
chemical_names: Tetrahydronaphthalenes
chemical_names: Variant Surface Glycoproteins, Trypanosoma
chemical_names: equisetin
citation:   Patham, B and Duffy, J and Lane, A and Davis, RC and Wipf, P and Fewell, SW and Brodsky, JL and Mensa-Wilmot, K  (2009) Post-translational import of protein into the endoplasmic reticulum of a trypanosome: An in vitro system for discovery of anti-trypanosomal chemical entities.  Biochemical Journal, 419 (2).  507 - 517.  ISSN 0264-6021     
document_url: http://d-scholarship-dev.library.pitt.edu/18942/1/licence.txt