Scientists have discovered a cunning new method to prevent the protein clumps that clog neurons in sufferers of Alzheimer's disease. By binding a small drug to a large protein, they can keep the clumps from forming. The technique holds promise for treating many diseases involving protein-protein interactions.
In Alzheimer's disease, large, abnormal clumps of a peptide called β amyloid surround and choke the insides of neurons. Hoping to retard the disease, researchers have tried using drugs to block such clumping, but with little success. Using Lilliputian drug molecules as blockers for relatively massive amyloid peptides is like trying to prevent strips of Velcro from adhering by sprinkling them with salt.
Molecular biologist Isabella Graef, chemist Jason Gestwicki, and biologist Gerald Crabtree of Stanford University adapted a blocking strategy found in nature to create a drug that seems to work. Gestwicki chemically tethered a synthetic ligand for FKBP--a large binding protein that soil bacteria use to cripple enzymes in bacterial foes--to Congo red, a dye that sticks to β amyloid. The resulting small molecule could grab FKBP on one end and β amyloid at the other and thus usher the bulky protein in between two amyloid peptides. When added to test tubes of β amyloid along with FKBP, the compounds either greatly delayed or completely prevented large clumps of β amyloid from forming. Without FKBP, however, the drug held no advantage, showing that the large protein is critical to its modus operandi. The smaller peptide clumps that formed also appeared less toxic to neurons. The drug, along with FKBP, also prevented β amyloid from killing most cultured rat neurons, the researchers report in the 29 October issue of Science.
The current form of the drug has no clinical utility in Alzheimer's disease, as Congo red does not cross the blood-brain barrier, but the technique could be useful for treating many diseases, including Alzheimer's and Parkinson's, that involve protein-protein interactions. "We think the idea of fighting protein bulk with protein bulk is going to be general," says Gestwicki. "It's like fighting fire with fire."
"They've played a creative chemical trick that clearly could be practical," says Peter Lansbury, a chemist at Harvard Medical School in Boston, "but the path from this to an Alzheimer's drug is going to be extremely difficult." One huge problem, Lansbury says, will be finding an alternative to Congo red that targets β amyloid.