A class of drugs being tested for Alzheimer’s disease has proved to work in an unexpected and highly specific way, opening up new possibilities for treating Alzheimer’s and many other diseases.
Some anti-inflammatory drugs, such as ibuprofen, reduce the buildup of a type of beta-amyloid protein that tends to form plaques in the brains of Alzheimer’s patients. Because this protein is produced when an enzyme, called gamma-secretase, slices up a larger protein, amyloid precursor protein (APP), the drugs were assumed to be acting on the enzyme itself and became known as gamma-secretase modulators, or GSMs.
Researchers at the Mayo Clinic in Jacksonville, Fla., have developed one such drug called tarenflurbil that is now in clinical trials. Results in the April 2008 issue of Lancet Neurology show benefit in patients with mild cases of Alzheimer’s disease.
In the June 12 Nature, the team used ultraviolet light to pinpoint where a tarenflurbil derivative, and one other GSM, exert their effects. “We were completely surprised by what we found,” says Thomas Kukar of the Mayo Clinic. The GSMs did not target gamma-secretase at all. Rather they acted on the substrate— the protein, APP in this case, which the enzyme binds and chops up.
“Virtually all drugs now in clinical use either block an enzyme’s action or bind to a receptor on a cell,” either of which can have serious side effects, says Kukar. “Focusing on the substrates may give us a whole new set of drug targets to go after.”