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

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

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Patham, B
Duffy, J
Lane, A
Davis, RC
Wipf, Ppwipf@pitt.eduPWIPF
Fewell, SW
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Mensa-Wilmot, K
Date: 15 April 2009
Date Type: Publication
Journal or Publication Title: Biochemical Journal
Volume: 419
Number: 2
Page Range: 507 - 517
DOI or Unique Handle: 10.1042/bj20081787
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0264-6021
MeSH Headings: Animals; Endoplasmic Reticulum--metabolism; HeLa Cells; Humans; Naphthalenes--pharmacology; Protein Transport--drug effects; Pyrrolidinones--pharmacology; Rats; Tetrahydronaphthalenes--pharmacology; Trypanosoma brucei brucei--metabolism; Variant Surface Glycoproteins, Trypanosoma--genetics; Variant Surface Glycoproteins, Trypanosoma--metabolism
Other ID: NLM NIHMS140541, NLM PMC2769561
PubMed Central ID: PMC2769561
PubMed ID: 19196237
Date Deposited: 12 Jun 2013 20:29
Last Modified: 12 Jun 2021 22:55
URI: http://d-scholarship-dev.library.pitt.edu/id/eprint/18942

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