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It's one thing to discover a bioactive compound and quite another to figure out how it works. Identifying the protein target with which a molecule interacts is considered a bottleneck in drug discovery, but it's often an important prerequisite for improving a drug's properties and gaining a better understanding of its molecular mechanism of action.
Researchers have now devised a way to use tens of thousands of genetically modified worms to identify protein targets of specific bioactive agents. The technique is a promising alternative to existing target identification techniques. The worm-based approach was developed and demonstrated by assistant professor of medical genetics and microbiology Peter J. Roy of the University of Toronto and coworkers (Nature 2006, 441, 91).
"Target identification has been one of the thorniest problems in small-molecule screening, so this is a welcome and encouraging advance," says assistant professor of medicine Randall T. Peterson of Massachusetts General Hospital, Boston, who earlier screened small molecules for bioactivity—but not targets—in another living system, zebrafish embryos. "The notion of using genetics to identify small-molecule targets is an old one, but this is a really elegant example of using that approach in a new organism, and indeed the first multicellular one."
Roy and coworkers first screened thousands of small molecules to see which ones affected wild-type Caenorhabditis elegans worms in some way—inducing a change in the worms' shape, for example. They then selected one of these bioactive compounds, nemadipine-A, and screened it against worms with widely varied gene modifications. In this "genetic suppressor screen," mutant worms genetically resistant to the bioactive compound were identified.
When the nemadipine-resistant worms' genetic mutations were mapped, the same gene turned out to be modified in each one, suggesting that the protein expressed by that gene, an L-type calcium channel α1-subunit, is the compound's molecular target. Antihypertension drugs closely resembling nemadipine are known to hit that target, helping to confirm the finding.
Target identification can currently be done in other ways-using genetic techniques such as expression profiling, expression cloning, yeast three-hybrid assays, and screening of yeast mutants. But none works in all situations.
The new approach also has limitations: Its applicability is restricted to compounds whose bioactivity is observable in whole organisms, and it's limited (for drug discovery purposes) to protein targets that function similarly in worms and humans. Its major advantages? "You're already working in the context of the whole animal, which is where you ultimately want to end up, and it's so simple I could teach a first-year undergrad to do it," Roy says.
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