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Weighty Discovery: Chemical screening technique identifies potential anthrax drug

11:03am, June 9, 2004
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Pharmaceutical and biotech firms, which spend billions of dollars every year searching for new drugs, keep an eye open for technologies to make their drug screening more fruitful. Chemists at the University of Chicago report a new screening method, which they've already used to identify a candidate compound for treating anthrax.

The discovery of new drugs is a tedious process with many complicated steps, says lead investigator Milan Mrksich. Most screening of chemicals relies on fluorescent labels that indicate when a chemical binds to a disease-related protein or some other target molecule. Because these labels can interfere with the activity of the target, however, the strategy is vulnerable to false positives, pointing to chemicals that turn out to be useless, says Mrksich. The problem stems from the size of the labels. "It's like having a 6-foot-wide mirror attached to the side of your car," he says.

To circumvent the use of fluorescent labels, Mrksich and his colleagues developed a strategy that judges a chemical's potential by measuring the mass of the product that results from its reaction with a target. The technique uses an instrument called a mass spectrometer, which is widely used for identifying molecules by essentially weighing them (SN: 10/19/02, p. 245: Available to subscribers at Nobel Chemistry: Laureates' techniques enable researchers to probe large biomolecules).

To adapt the instrument for rapidly screening thousands of potential anthrax drugs, the Chicago team custom-designed a biochip. The glass chip harbors an array of 400 reaction wells. Each well is coated with gold that's topped with a layer of organic molecules. Bound to these molecules is a protein fragment, or peptide, that gets cleaved in two in the presence of anthrax lethal factor, a toxin produced by the bacterium.

To begin the screening process, the researchers added to each well the toxin along with one of thousands of small molecules from a library of potential drug candidates. This is where the mass spectrometer came in. With a laser, the instrument zapped each well, one at a time, sputtering its contents into the instrument's chamber. A peptide that measures out to its full mass is a positive result because it indicates that the toxin's protein-snipping action was blocked.

After screening 10,000 chemicals in 3 days, the researchers found one compound, called DS-998, that blocked the activity of anthrax lethal factor. In a subsequent test, the compound protected lab-grown human cells that later were exposed to the toxin. The researchers describe their experiment in the June Nature Biotechnology. Some drug companies already have expressed interest in DS-998, says Mrksich.

Peter Seeberger of the Swiss Federal Institute of Technology in Zurich finds the results "impressive" and says the technique could have broad applications. For example, he says, the method could be adapted to analyze biomolecules that interfere with carbohydrates that are central to some cancers and infectious diseases.

The Chicago researchers are now using the method to screen for potential cancer therapies.

Because mass spectrometry is less prone to false positives than existing technologies are, it could shorten the overall time to develop a new drug, says Mrksich. By automating the process with robotic equipment, the technique could screen on the order of 50,000 chemicals a day, a rate that approaches that of current methods, he adds.

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