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    R. Kiplin Guy, PhD

    Chemists tackle brain degeneration disease

    A St. Jude investigator was a key player in a national team of researchers that brought scientists a step closer to finding a cure for brain-degeneration diseases caused by abnormal proteins called prions.

    Prions, which occur naturally, cause brain damage when they undergo a certain shape change. The disease they cause in humans, called Creutzfeldt-Jakob disease, has a more infamous cousin on the farm called mad cow disease.

    Previously, researchers found that an anti-malaria drug called quinacrine appeared to be effective in blocking prion formation. But as is common with new drugs—or old drugs being considered for new uses—the basic molecule had problems that made it less than ideal as a treatment. Quinacrine was too toxic; it triggered a special pump in brain cells that pushed the drug out before it could block new prion formation.

    Kip Guy, PhD, Chemical Biology and Therapeutics chair, and his colleagues wanted to figure out how to modify quinacrine so that it would work effectively and safely. Chemists in Guy’s lab studied which parts of the molecule make it block prions and which parts make it toxic or cause it to trigger the cell pump.

    Guy’s laboratory made 144 unique molecules that are related to quinacrine but have a variety of different atoms or molecules attached to specific parts of the drug’s basic structure. Then the team tested how the molecules worked by putting them into special cells that had been infected with prions; by doing this, the scientists could see which drugs, if any, would block new prion formation without hurting the cells.

    The team discovered a specific spot on the quinacrine molecule that makes it toxic in cells; the researchers also discovered two areas that determine how effectively the drug blocks new prion formation.

    “This work provided a basic blueprint that will guide us as we try to redesign quinacrine at specific spots to make it the most effective, safest drug possible against prion diseases,” Guy said. Guy is senior author of a report on this work that appeared in the September issue of Bioorganic & Medicinal Chemistry Letters.

    November 2006

    St. Jude does both laboratory and clinical research in order to find cures for catastrophic diseases of children. Much of this research, especially in the laboratory, leads to discoveries of the basic workings of the body's cells. Therefore, some of our work has broader implications than childhood diseases and provides insights into adult diseases as well.