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A high‐throughput screen for inhibitors of xenobiotic detoxification in nematodes
Author(s) -
Leung Chi Kwan,
Deonarine Andrew Stevenson,
Choe Keith Patrick
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.998.3
Subject(s) - biology , xenobiotic , transcription factor , detoxification (alternative medicine) , high throughput screening , genetic screen , drug discovery , multiple drug resistance , drug resistance , microbiology and biotechnology , gene , computational biology , genetics , enzyme , biochemistry , mutant , medicine , alternative medicine , pathology
Multidrug resistance is a growing problem in parasitic nematodes. In pathogens and tumor cells, multidrug resistance is mediated by enzymes that detoxify xenobiotics. The transcription factor SKN‐1 activates detoxification genes and is essential for development in C. elegans. Pharmacological compounds that target SKN‐1 would provide new tools for studying multidrug resistance and have the potential to inhibit embryonic development and drug resistance in adults. We identified the WD40 repeat protein WDR‐23 as a potent regulator of SKN‐1. Importantly, the homologous mammalian transcription factor Nrf2 is regulated by a distinct pathway and binds DNA by a distinct mechanism. We propose WDR‐23/SKN‐1 as a promising target for drugs that inhibit embryonic development, xenobiotic detoxification, and drug resistance in nematodes without affecting mammalian hosts. The small size, simple culturing characteristics, and genetic tractability of C. elegans make it an ideal system to screen for SKN‐1 inhibitors. We have developed a fluorescent‐based 1536‐well plate assay to measure SKN‐1 activity in C. elegans. Pilot screens with the Spectrum library and Library of Pharmacologically Active Compounds (LOPAC1280) indicate that our assay is amenable for HTS in whole animals. Inhibitors would provide tools for studying the function of SKN‐1 in parasitic species. This work is funded by NIH grant R21NS067678‐01.