A small-molecule screen in C. elegans yields a new calcium channel antagonist.

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.

• Authors: Trevor C Y Kwok, Nicole Ricker, Regina Fraser, Allen W Chan, Andrew Burns, Elise F Stanley, Peter McCourt, Sean R Cutler, Peter J Roy
• Journal: Nature (Nature) Vol. 441 Issue 7089 Pg. 91-5 (May 04 2006) ISSN: 1476-4687 [Electronic] England
• PMID: 16672971 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Calcium Channels, L-Type
• Pyridines
• nemadipine-A
• Felodipine

Topics

• Animals
• Caenorhabditis elegans (drug effects, embryology, genetics, physiology)
• Calcium Channel Blockers (chemistry, isolation & purification, pharmacokinetics, pharmacology)
• Calcium Channels, L-Type (metabolism)
• Drug Evaluation, Preclinical (methods)
• Felodipine (isolation & purification, pharmacokinetics, pharmacology)
• Oviposition (drug effects)
• Phenotype
• Pyridines (chemistry, isolation & purification, pharmacology)