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

Nature. 2006 May 4;441(7089):91-5. doi: 10.1038/nature04657.


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.

Publication types

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

MeSH terms

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


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