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

Author

Chi K Leung, Ying Wang, Siobhan Malany, Andrew Deonarine, Kevin Nguyen, Stefan Vasile, and Keith P Choe

Subjects
Medicine, Science
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.

Published
2013
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2. An ultra high-throughput, whole-animal screen for small molecule modulators of a specific genetic pathway in Caenorhabditis elegans

Author

Kevin Nguyen, Ying Wang, Chi K. Leung, Siobhan Malany, Stefan Vasile, Keith P. Choe, and Andrew Deonarine

Subjects
Drugs and Devices, Drug Research and Development, High-throughput screening, Science, DNA transcription, Drug Evaluation, Preclinical, Computational biology, Small Molecule Libraries, 03 medical and health sciences, Model Organisms, Molecular cell biology, 0302 clinical medicine, Drug Stability, Chemical Biology, Drug Discovery, High-Throughput Screening Assays, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Biology, Gene, Cellular Stress Responses, 030304 developmental biology, Acrylamide, 0303 health sciences, Multidisciplinary, Dose-Response Relationship, Drug, biology, Drug discovery, Animal Models, biology.organism_classification, Small molecule, Molecular biology, Chemistry, Oxidative Stress, Gene Expression Regulation, 030220 oncology & carcinogenesis, Tetradecanoylphorbol Acetate, Medicine, Gene expression, Medicinal Chemistry, Heat-Shock Response, Research Article, Genetic screen
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.

Published
2013

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