Biochemical braces
Loren Walensky (below) helped build a tiny "staple" to reinforce a compound involved in cancer cell death. The computerized image above shows the unstapled and stapled compound.
Illustration by Nicole Bedard
Within every cell in the body, there is a contest for that cell's future. Specialized proteins order it to die, while others instruct it to continue living. The cell's course is dictated by the relative strength of these commands.
The vast majority of the time, there is a natural balance between the death of old cells and the creation of new ones. When the death mechanism fails because of a faulty gene, cells may persist long past the end of their natural lifespan. The resulting clump of cells can form a tumor.
"In one of the classic models of cancer, cells produce an oversupply of survival proteins, which act as a shield against other proteins that signal the cell to die," says Loren Walensky, MD, PhD, who joined Dana-Farber as its first chemical biologist in 2003. "The challenge is to find a way of restarting the death process."
Ideally, scientists could do that by disrupting the "blockade" that survival proteins exert on the cell's death machinery. But the structural complexity of such proteins and their location deep within the cell nucleus have made it difficult to design drugs with that ability.
Walensky and his colleagues knew that a protein called BID has a short, coiled segment — a helical peptide — that is capable of triggering the natural cell-death process, called apoptosis. When the peptide is produced in the laboratory, artificially disconnected from the entire protein, it loses its helical shape, which prevents it from entering cells to deliver its "die" message.
With Verdine and Stanley J. Korsmeyer, MD, the late chairman of Dana-Farber's Executive Committee for Research, Walensky constructed a tiny "staple" from synthetic amino acids (the building blocks of proteins) to reinforce the natural peptide. In laboratory tests, the stapled peptides entered leukemia cells and activated their cell-death program. Even more intriguing, when the strengthened peptides were injected into mice with human-type leukemia, the disease was suppressed.
The experiments demonstrated that stapled peptides can be used to study how proteins interact within cells, and to block interactions that lead to disease. "Stapling enables us to generate a brand-new 'molecular toolbox' for probing and potentially treating the fundamental causes of cancer and other diseases," Walensky remarks. Using the stapled peptide, Walensky recently proved that BID sets the cell's death machinery in motion by binding to a protein called BAX, vindicating a theory first proposed by Stanley Korsmeyer. The finding has energized efforts to treat some cancers with molecules able to latch onto BAX.
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