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Vol. 344 ,
- 17 April 2014 12:48 pm , Vol. 344 , #6181
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Big Signal from a Small Molecule
9 July 1998 8:00 pm
Drug companies would love to find small compounds that mimic the effects of protein drugs yet evade breakdown in the digestive tract. Now scientists have taken a first step by discovering a small molecule that performs such a trick in mice. The new compound, described in tomorrow's Science, mimics the action of a protein that triggers the growth of white blood cells.
Many protein drugs--including insulin and other hormones known as cytokines--stick snugly to large surfaces on their receptors. That made researchers worry that small chemicals--which might be just 2% of a protein's size--would be too puny to turn on such receptors. But there was hope: When cytokines bind to their receptors, they drag the receptors together into pairs called dimers. That aggregation seems to be what turns on a receptor, and small molecules, such as a peptide, just might be able to do the trick.
A team of researchers at Ligand Pharmaceuticals in San Diego and SmithKline Beecham Pharmaceuticals in Collegeville and King of Prussia, Pennsylvania, wanted to find a mimic of granulocyte-colony-stimulating factor (G-CSF), which is commonly used to boost patients' immune systems after chemotherapy. To speed the search, the team had engineered a line of mouse cells to test for G-CSF-like activity. When G-CSF activates its receptor, it ultimately activates proteins called STATs; the team engineered the cells to churn out the light-generating protein luciferase, which would be turned on by the STAT molecules. The researchers then treated mouse cells with thousands of compounds and picked out the ones that made the cells glow. They hit upon a small organic compound called SB 247464 that stimulated the growth of mouse white blood cells in culture and in living mice.
Although SB 247464 doesn't work with human cells, the discovery will spur the pharmaceutical industry's search for protein-mimicking drugs, says Mark Goldsmith, who studies cytokine receptors at the University of California, San Francisco. It suggests, he adds, that with small molecules, "we can mimic many interactions that just a few years ago would have been expected to be much more difficult."