Scientists from the University of California have discovered three molecules that show great potential in the development of new Alzheimer's drugs. The new therapy targets a protein that accumulates in Alzheimer's victims effectively curing the patient.
The team of scientists discovered three molecules from a search of 58 000, that appear to inhibit a key perpetrator of Alzheimer's disease. The perpetrator - a protein called "tau" - becomes tangled in the brains of patients with Alzheimer's,
"Tau goes wrong and becomes pathological when it becomes intensely phosphorylated," said Ken Kosik, co-director of the Neuroscience Research Institute at the University of California and head of the effort to find these molecules.
"This means that many phosphate groups attach to tau - modify it - and cause it to become dysfunctional," he added.
Kosik and his team focused on the neurofibrillary tangles of neurons made of tau in the brain that, along with senile plaques, characterise Alzheimer's disease. CDK5, an enzyme that attaches the phosphate to the tau protein, facilitates the disease process. The aim was to find a way to inhibit this enzyme, keeping it from putting any phosphate on tau.
Kosik's laboratory started by purifying the enzyme as well as the tau protein. They then watched tau become phosphorylated by the enzyme. The researchers then performed a library search of small molecules (58,000 of them) in an attempt to find those that would prevent phosphorylation.
Small molecules are preferred because they are more easily used as a drug since they can get through the body and into cells. It is also important to find molecules that will cross the blood brain barrier.
Kosik said that proteins are strings of amino acids folded into small globs. All proteins that happen to be an enzyme involved in phosphorylation have one thing in common. They have a pocket that is almost always in the same place and this is where the phosphate attaches to the enzyme, in this case CDK5. To get a molecule that specifically prevents the enzyme from binding at the pocket is difficult.
Of the three compounds, the research group found, the scientists were able to locate where they bind. They found that one binds in the pocket, another binds at the edge of the pocket, and a third appears to bind completely outside the pocket. The scientists are most interested in the second and third compounds.
"This is the first demonstration that we can find small molecules that can more specifically affect the phosphorylation of tau by CDK5," said Kosik.
In terms of future directions, Kosik said: "There is lots to do here, lab testing, testing in animals, etc. But we have made an important step forward toward developing treatments for this disease."
He noted that this work is of a type usually performed by pharmaceutical companies, but in this case was completed in an academic environment.
"There are a couple of FDA-approved drugs that help a little, but don't modify the disease. They give a little bit of symptomatic relief, but don't change the inexorable progression of the disease," Kosik said.
The drugs are Tacrine ( Cognex ) and Donezepil ( Aricept ).Tacrine prevents the breakdown of acetylcholine, a brain chemical needed for normal memory and learning. It frequently produces a modest improvement in symptoms, increasing alertness and thinking skills. However, it's temporary - the drug doesn't significantly alter the course of disease - and it commonly causes gastrointestinal side effects, such as nausea, vomiting and diarrhea. More worrisome, it can cause liver damage. Patients must have regular blood monitoring to avoid liver problems.
Donezepil, like tacrine, boosts acetylecholine, with equally effective results. In addition, it produces fewer GI side effects, doesn't cause liver damage and is taken once a day vs. the troublesome four-times-a-day regimen of tacrine. Consequently, almost all patients now start out on Aricept.
The results of the study are published in the July issue of the journal Chemistry and Biology, released on Friday, July 22.