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Molecular staples shape a cancer killer

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"Academic and industrial laboratories are engaged in a Herculean effort to develop new molecules that reactivate the apoptotic program in tumor cells," wrote HHMI investigator Steven F. Dowdy of the University of California, San Diego, in a Perspectives article that was published in the same issue of Science.

Korsmeyer, Walensky, and their colleagues aimed to construct a key regulatory segment of an apoptosis-triggering protein called BID that could induce apoptosis in cancer cells. Their objective was to create a short peptide that functionally mimicked the specific region of the BID protein that elicits cell death. Theoretically, such a small molecule -- basically a short string of amino acids -- could insinuate itself into cancer cells to trigger their suicide.

"Our goal was to modify the natural peptide sequence only enough to stabilize or reinforce its shape to improve its pharmacological properties," said Walensky. The researchers used the hydrocarbon stapling strategy to brace the peptide from within.

"We substituted non-natural amino acids for natural amino acids in selected positions," he said. "The non-natural amino acids look very similar to the natural ones, except that they include hydrocarbons that can be cross-linked to one another. This cross-linking provides a constraint, which doesn't allow the peptide to unfold." The researchers dubbed the engineered peptide "stabilized alpha-helix of BCL-2 domains" (SAHB). The BCL-2 family of proteins regulates apoptosis.

When the researchers examined SAHB's properties, they found that it assumed a stable alpha-helical shape, bound to the right protein to trigger apoptosis, and resisted degradation by proteases. They also found that SAHB specifically triggered the cell's power plants, the mitochondria, to release a protein that participates in launching apoptotic destruction.

Their experiments with leukemia cells cultured in the laboratory revealed that SAHB could enter,
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
2-Sep-2004


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