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Molecular staples shape a cancer killer

and, more importantly, inhibit the growth of those cells.

"When we saw that we could activate cell death in a specific way in whole cells, we were eager to conduct animal studies," said Walensky. So, the researchers tested the effects of SAHB on mice that harbored human leukemia cells. "We found that SAHB treatment effectively suppressed leukemia in these mice," he said.

According to Walensky, the experiments are the first steps in a broader effort to construct hydrocarbon-stapled alpha-helical peptides that affect many control points of apoptosis. These are necessary because different cancers may have thwarted the apoptotic machinery in different ways, he said.

"The goal would be to use the natural sequences of these pro-apoptotic peptides to try to specifically activate the cell death program in a resistant cell," said Walensky. "For example, certain lymphomas are specifically driven by BCL-2 overexpression. So, if you could knock down some of the impact of that BCL-2, you would tip that lymphoma cell over the edge toward death."

Korsmeyer, Walensky, and their colleagues are now developing and testing different hydrocarbon-stapled BH3 domains against a range of cancer cells. Ultimately, they believe that further development of these peptides could broaden the arsenal of compounds used to kill different cancers.

Walensky said he would not be surprised to see hydrocarbon stapling of alpha-helices applied to control many interactions between proteins. "The alpha-helix plays a pivotal role in many biological interactions," said Walensky. "So if we could target protein-protein interactions at critical biological control points using the natural, evolutionarily derived sequence for that protein target -- with just this minor modification of hydrocarbon stapling -- then we might have a whole new set of tools to study and manipulate protein interactions within cells."


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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
2-Sep-2004


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