Key Points
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The nematode Caenorhabditis elegans has become a widely used model organism in academic and industrial research. This is the result of its ease of cultivation and maintenance, short lifespan, fully sequenced genome, advanced genetic toolkit, complete description of cell lineage, simple nervous system, as well as its suitability for high-throughput genetic and chemical screening.
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A chemistry-to-gene screen is a forward genetic approach in which mutagenized C. elegans worms are screened for resistance to a particular compound. The resulting mutations are mapped to identify genes underlying resistance.
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Chemistry-to-gene screens have successfully defined the molecular targets of drugs controlling nematode parasites, such as levamisole, aldicarb, benzimidazoles and ivermectin. They have also revealed targets of human drugs such as nicotine, alcohol and volatile anaesthetics.
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RNA interference (RNAi) is a reverse genetic approach highly suitable for gene-to-chemistry screens. RNAi has now been refined in C. elegans to the extent that it provides a very tractable, high-throughput tool that has considerable potential to define and validate the genetic basis of drug action.
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Screens on mutant worms have provided a proof of principle for the use of C. elegans in screening for candidate drugs to treat human diseases.
Abstract
The nematode worm Caenorhabditis elegans is a genetic model organism linked to an impressive portfolio of fundamental discoveries in biology. This free-living nematode, which can be easily and inexpensively grown in the laboratory, is also a natural vehicle for screening for drugs that are active against nematode parasites. Here, we show that chemistry-to-gene screens using this animal model can define targets of antiparasitic drugs, identify novel candidate drug targets and contribute to the discovery of new drugs for treating human diseases.
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Glossary
- ANTHELMINTIC
-
A chemical that controls parasitic worms. An example is levamisole, which controls parasitic nematodes.
- ENDECTOCIDE
-
An antiparasitic drug which controls both internal parasites (such as worms) and external parasites (such as ticks). An example is ivermectin.
- CHEMISTRY-TO-GENE SCREEN
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Following mutagenesis of C. elegans, mutants are screened for resistance to a particular chemical and the resulting mutations are mapped and identified (useful for identifying hitherto unknown drug targets).
- NICOTINIC ACETYLCHOLINE RECEPTORS
-
(nAChRs). Prototypical members of the cys-loop ligand-gated ion channel superfamily classified by the ability of nicotine to activate them. On binding acetylcholine, the natural neurotransmitter activating these receptors, the ion channel is opened transiently resulting in an influx of ions into the cell.
- CYS-LOOP LIGAND-GATED ION CHANNEL SUPERFAMILY
-
An extended family of ligand-gated ion channels, each molecule composed of five subunits arranged around an ion permeable channel. Each subunit is characterised by an extracellular domain containing the cys-loop – two disulfide bond-forming cysteines separated by 13 amino acid residues. Members include nAChRs and ionotropic receptors for GABA, 5-HT3 and glycine.
- ACARICIDE
-
A chemical that controls mites.
- RNA INTERFERENCE
-
(RNAi). The deployment of double-stranded RNA, which results in specific silencing of the corresponding gene through degradation of endogenous RNA.
- COPAS
-
An automated high throughput system that can sort C. elegans (up to 100,000 worms per hour) based on physical and optical parameters.
- TWO-HYBRID ANALYSIS
-
A large-scale yeast-two hybrid screen to identify protein– protein (or 'interactome') networks.
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Jones, A., Buckingham, S. & Sattelle, D. Chemistry-to-gene screens in Caenorhabditis elegans. Nat Rev Drug Discov 4, 321–330 (2005). https://doi.org/10.1038/nrd1692
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DOI: https://doi.org/10.1038/nrd1692
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