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New approach offers potential drug-discovery shortcut

Researchers at Massachusetts General Hospital have developed a way of identifying promising new drugs that may get around a major challenge in drug discovery. In the May issue of Nature Biotechnology the team from the MGH Cardiovascular Research Center (CVRC) describes using an animal model to screen for a compound that suppresses a serious genetic mutation. Their success did not rely on first identifying a molecular target for the new drug, something that is a key bottleneck in current procedures. The study is being released today on the journal's website.

"Currently most drugs are designed to act on a specific protein, but for most diseases we still don't know what the protein targets should be," says Randall Peterson, PhD, of the MGH CVRC, the paper's lead author. "This is a totally different approach that shows how, without knowing the best target, you can screen for drugs that could reverse a disease and in the process learn something new about the underlying biology."

The researchers started with embryos of zebrafish a tiny tropical fish used as a model of vertebrate development with a mutation called gridlock, which prevents the correct development of the circulatory system in the lower portion of the body. A panel of these embryos was exposed to a very diverse library of small molecules 5,000 in all to see if any would prevent expression of the gridlock mutation. Two similar molecules were identified that suppressed the mutation, allowing the embryos to develop normally. The one that appeared more powerful, called GS4012, was chosen for further study.

The gridlock-suppressing effects of GS4012 were found to vary with dosage, and no vascular abnormalities were seen at the doses studied. Application of the compound appeared to be most effective at a developmental stage right before and during the formation of major vascular structures. Further experiments showed that GS4012 appears to promote the activity of the angiogene
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Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
18-Apr-2004


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