An ultra high-throughput, whole-animal screen for small molecule modulators of a specific genetic pathway in Caenorhabditis elegans

PLoS One. 2013 Apr 29;8(4):e62166. doi: 10.1371/journal.pone.0062166. Print 2013.

Abstract

High-throughput screening (HTS) is a powerful approach to drug discovery, but many lead compounds are found to be unsuitable for use in vivo after initial screening. Screening in small animals like C. elegans can help avoid these problems, but this system has been limited to screens with low-throughput or no specific molecular target. We report the first in vivo 1536-well plate assay for a specific genetic pathway in C. elegans. Our assay measures induction of a gene regulated by SKN-1, a master regulator of detoxification genes. SKN-1 inhibitors will be used to study and potentially reverse multidrug resistance in parasitic nematodes. Screens of two small commercial libraries and the full Molecular Libraries Small Molecule Repository (MLSMR) of ∼364,000 compounds validate our platform for ultra HTS. Our platform overcomes current limitations of many whole-animal screens and can be widely adopted for other inducible genetic pathways in nematodes and humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acrylamide / pharmacology
  • Animals
  • Caenorhabditis elegans / drug effects*
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans / physiology
  • Caenorhabditis elegans Proteins / genetics
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods*
  • Drug Stability
  • Gene Expression Regulation / drug effects
  • Heat-Shock Response / drug effects
  • Heat-Shock Response / genetics
  • High-Throughput Screening Assays / methods*
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Small Molecule Libraries / pharmacology*
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Caenorhabditis elegans Proteins
  • Small Molecule Libraries
  • Acrylamide
  • Tetradecanoylphorbol Acetate