NEWS OF THE WEEK DRUG
DISCOVERY
WORMING YOUR WAY TO DRUG TARGETS
ing genetic techniques such as expression profiling, expression cloning, yeast three-hybrid assays, and screening ofyeast mutants. But none works in all situations. T h e new approach also has
Worms are used to rapidly identify protein targets of bioactive agents
I
T'S ONE THING TO DISCOVER
a bioactive compound and quite another to figure out how it works. Identifying the protein tar get with which a molecule interacts is considered a bottleneck in drug discovery, but it's often an impor tant prerequisite for improving a drug's properties and gaining a bet ter 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 ge netics and microbiology Peter J. Roy of the University of Toronto and coworkers {Nature 2 0 0 6 , 441, 91). "Target identification has been one of the thorniest problems in small-molecule screening, so this is a welcome and encouraging ad vance," 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 smallmolecule targets is an old one, but this is a really elegant example of using that approach in a new or ganism, and indeed the first mul ticellular one." R o y a n d c o w o r k e r s first screened thousands of small mol ecules to see which ones affected wild-type Caenorhabditis elegans worms in some way—inducing a change in the worms' shape, for WWW.CEN-0NLINE.ORG
Randomly mutagenized worms
Resistant worm
:ir
I Protective i gene Chromosome
\ example. They then select Protein ed one of these bioactive target compounds, nemadipineW O R M ID The new worm-based target identification A, and screened it against approach has four steps: 1. Expose mutant worms to worms with widely varied bioactive compound (yellow wedge). 2. Isolate unaffected gene modifications. In this worms. 3. Map unaffected worms' genomes to identify "genetic suppressor screen," protective gene mutations. U. Use other tests to verify mutant worms genetically re that proteins expressed by protective genes are targets sistant to the bioactive com of the compound. pound were identified. W h e n the nemadipinelimitations: Its applicability is re resistant worms' genetic muta stricted to compounds whose bio tions were mapped, the same gene activity is observable in whole or turned out to be modified in each ganisms, and it's limited (for drug one, suggesting that the protein discovery purposes) to protein expressed by that gene, an L-type targets that function similarly in calcium channel oq-subunit, is the worms and humans. Its major ad compound's molecular target. vantages? "You're already working Antihypertension drugs closely in the context of the whole animal, resembling nemadipine are known which is where you ultimately want to hit that target, helping to con to end up, and it's so simple I could firm the finding. teach a first-year undergrad to do Target identification can cur it," Roy says.—STU BORMAN rently be done in other ways—usBUSINESS
Clariant Exits Pharma Chemicals ecoming the latest big chemical maker to leave the fine chemicals business, spe cialties firm Clariant has agreed to sell its Pharmaceutical Fine Chemicals unit to the pri vate equity firm TowerBrook Capital Partners. The sale price is about $88 million, $32 million of which won't be paid for two years. The Pharmaceutical Fine Chemicals business had 2005 sales of around $168 million. It includes much of the former BTP, a company that Clariant acquired for $1.8 billion in 2000 at the height of the chemical industry's love affair with pharmaceuti cal chemical production. Since then, growth and profits in the field have plummeted, prompting firms such as Avecia and Rhodia to leave. Avecia sold its pharma ceutical custom synthesis business to Nicholas Piramal India Ltd. late last year, while Rhodia recently sold its Pharmaceutical Solutions
Β
unit to Shasun Chemicals & Drugs, also of India. Lanxess has put its custom manufacturing business into a separate subsidiary called Saltigo, although the German company maintains that the move is not a prelude to a sale. Clariant says its sale to TowerBrook will cre ate one of the world's largest businesses based solely on pharmaceutical fine chemicals. The new company will have about 800 employees; plants in Italy, Germany, the U.K., and the U.S.; and head quarters in Frankfurt am Main, Germany. TowerBrook Managing Director James Har rison says the Pharmaceutical Fine Chemicals business is well-positioned to benefit from what he calls an increasing trend to outsourcing. "To gether with management, we plan to grow the business through new capital investment and through appropriate acquisitions," he says.— MICHAEL MCCOY
C & E N / MAY 8, 2006
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