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Molecular staples shape a cancer killer

Howard Hughes Medical Institute (HHMI) researchers have successfully designed and improved a new type of cancer-killing compound by performing molecular surgery to stabilize the molecule so that it selectively triggers cell death.

The idea for developing the compound emerged from the HHMI laboratory of Stanley J. Korsmeyer, who leads one of the hottest research teams currently studying programmed cell death, or apoptosis, a genetic program that executes cells that are no longer needed. Using the biologically active portion of a protein that triggers apoptosis, Korsmeyer's team successfully inserted non-natural amino acids into the peptide sequence and then performed a chemical reaction that created a "staple" within the molecule, resulting in its stabilization. Korsmeyer and the paper's lead author, Loren D. Walensky, who are at the Dana-Farber Cancer Institute at Harvard Medical School, reported their studies in the September 3, 2004, issue of the journal Science.

The chemical approach they applied, called hydrocarbon stapling, was developed by their collaborator Gregory L. Verdine of Harvard University, and permitted the researchers to overcome the tendency of short peptides to lose their critical three-dimensional structure and their ability to kill cells -- when removed from the context of the complete protein. This has been one of the greatest obstacles associated with using short peptides as therapeutic agents, and has hindered their legitimacy as pharmaceutical lead compounds. By making the peptides more resistant to degradation and enabling their cellular uptake, the hydrocarbon staple overcomes classic shortcomings of peptide therapeutics.

As the molecular events that lead to execution and death have become clearer during the last decade, researchers speculated that it would not be long before biotechnology and pharmaceutical companies were racing to develop novel compounds that could be used to hasten or prevent the demise of c
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
2-Sep-2004


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