A Small-molecule Screen in C. Elegans Yields a New Calcium Channel Antagonist.
From: Department of Medical Genetics and Microbiology, and The Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
Nature
- Publish Date: May 2006
- ISSN: 1476-4687
- Volume: 441
- Issue: 7089
- Pages: 91-5
- Medium: Internet
- Language: English
- Citation (JAMA): Kwok Trevor C Y, Ricker Nicole, Fraser Regina, et al. A Small-molecule Screen in C. Elegans Yields a New Calcium Channel Antagonist.. Nature May 2006;441:91-5
Abstract
Small-molecule inhibitors of protein function are powerful tools for biological analysis and can lead to the development of new drugs. However, a major bottleneck in generating useful small-molecule tools is target identification. Here we show that Caenorhabditis elegans can provide a platform for both the discovery of new bioactive compounds and target identification. We screened 14,100 small molecules for bioactivity in wild-type worms and identified 308 compounds that induce a variety of phenotypes. One compound that we named nemadipine-A induces marked defects in morphology and egg-laying. Nemadipine-A resembles a class of widely prescribed anti-hypertension drugs called the 1,4-dihydropyridines (DHPs) that antagonize the alpha1-subunit of L-type calcium channels. Through a genetic suppressor screen, we identified egl-19 as the sole candidate target of nemadipine-A, a conclusion that is supported by several additional lines of evidence. egl-19 encodes the only L-type calcium channel alpha1-subunit in the C. elegans genome. We show that nemadipine-A can also antagonize vertebrate L-type calcium channels, demonstrating that worms and vertebrates share the orthologous protein target. Conversely, FDA-approved DHPs fail to elicit robust phenotypes, making nemadipine-A a unique tool to screen for genetic interactions with this important class of drugs. Finally, we demonstrate the utility of nemadipine-A by using it to reveal redundancy among three calcium channels in the egg-laying circuit. Our study demonstrates that C. elegans enables rapid identification of new small-molecule tools and their targets.
Mesh Headings (Keywords): Animals, Caenorhabditis elegans, Calcium Channel Blockers, Calcium Channels, L-Type, Drug Evaluation, Preclinical, Felodipine, Oviposition, Phenotype, Pyridines
Check for Full Text / PubMed Unique Identifier (PMID): 16672971
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