An ultra high-throughput, whole-animal screen for small molecule modulators of a specific genetic pathway in Caenorhabditis elegans
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-through...
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| Veröffentlicht in: | PloS one 2013-04, Vol.8 (4), p.e62166 |
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| creator | Leung, Chi K Wang, Ying Malany, Siobhan Deonarine, Andrew Nguyen, Kevin Vasile, Stefan Choe, Keith P |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0062166 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0062166</identifier><identifier>PMID: 23637990</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acrylamide - pharmacology ; Animals ; Biology ; Caenorhabditis elegans ; Caenorhabditis elegans - drug effects ; Caenorhabditis elegans - genetics ; Caenorhabditis elegans - metabolism ; Caenorhabditis elegans - physiology ; Caenorhabditis elegans Proteins - genetics ; Chemistry ; Detoxification ; Dose-Response Relationship, Drug ; Drug discovery ; Drug Evaluation, Preclinical - methods ; Drug resistance ; Drug Stability ; Gene Expression Regulation - drug effects ; Heat-Shock Response - drug effects ; Heat-Shock Response - genetics ; High-throughput screening ; High-Throughput Screening Assays - methods ; Kinases ; Lead compounds ; Medicine ; Modulators ; Multidrug resistance ; Nematodes ; Oxidative Stress - drug effects ; Oxidative Stress - genetics ; Screening ; Small Molecule Libraries - pharmacology ; Tetradecanoylphorbol Acetate - pharmacology ; Worms</subject><ispartof>PloS one, 2013-04, Vol.8 (4), p.e62166</ispartof><rights>2013 Leung et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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| subjects | Acrylamide - pharmacology Animals Biology Caenorhabditis elegans Caenorhabditis elegans - drug effects Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans - physiology Caenorhabditis elegans Proteins - genetics Chemistry Detoxification Dose-Response Relationship, Drug Drug discovery Drug Evaluation, Preclinical - methods Drug resistance Drug Stability Gene Expression Regulation - drug effects Heat-Shock Response - drug effects Heat-Shock Response - genetics High-throughput screening High-Throughput Screening Assays - methods Kinases Lead compounds Medicine Modulators Multidrug resistance Nematodes Oxidative Stress - drug effects Oxidative Stress - genetics Screening Small Molecule Libraries - pharmacology Tetradecanoylphorbol Acetate - pharmacology Worms |
| title | An ultra high-throughput, whole-animal screen for small molecule modulators of a specific genetic pathway in Caenorhabditis elegans |
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