1. 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
2. Department of Botany, University of Toronto, 25 Willcocks Street, Toronto, Ontario M5S 3B2, Canada
3. Collaborative Program in Developmental Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario M5S 3G5, Canada
4. Department of Physiology and Toronto Western Research Institute, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
5. *These authors contributed equally to this work

Correspondence to: Peter J. Roy^1,3 Correspondence and requests for materials should be addressed to P.J.R. (Email: peter.roy@utoronto.ca).

Small-molecule inhibitors of protein function are powerful tools for biological analysis¹ 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 ₁-subunit of L-type calcium channels^{2, 3}. 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 ₁-subunit in the C. elegans genome^{4, 5}. 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.

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