Building on other recent work, Walensky sought to remove the alpha-helical BH3 subunit from the protein and use it as a sharply aimed tool to shut down the BCL-2 protein and activate the death pathway in cancer cells, without harming normal cells. If that proved successful, it would show that the BH3 alpha helix and alpha helices from many other proteins could be used like keys to turn off protein activity involved in disease processes.
These alpha helices then could serve as the foundation for building novel drugs. But one hurdle loomed. When the helical "death domain" is removed from its parent protein, it loses its rigid shape, becoming floppy liked an overstretched Slinky. In this form, it is vulnerable to degradation, unable to enter cells, and left powerless to block the antideath BCL-2 protein. Walensky's goal was to return the isolated amino acid helix to its original shape after its removal from the BH3-containing protein.
Drawing on his dual background in chemistry and cell biology, and applying a strategy developed by Verdine, who is a chemist, Walensky found the answer. First, he made synthetic amino acids that mimicked some of those within the helix. "Then we swapped out the natural amino acids and inserted the synthetic ones" at certain positions along the helix. Crucially, the artificial amino acids were linked to each other by a pair of hydrocarbon subunits. Like a reinforcing metal staple, Walensky e
Contact: Bill Schaller
Dana-Farber Cancer Institute