( ease and put them together. Kosik a...)Scientists discover that three molecules may be developed into new Alzheimer's drugs

Kosik and his team chose to focus on the neurofibrillary tangles of neurons in the brain that, along with senile plaques, characterize Alzheimer's disease. The tangles are made of "tau," a protein that is also present normally in the brain.

"Tau goes wrong and becomes pathological when it becomes intensely phosphorylated," said Kosik. "This means that many phosphate groups attach to tau--modify it--and cause it to become dysfunctional."

The culprit is an enzyme, called CDK5, that attaches the phosphate to the tau protein, facilitating the disease process. The researchers set out to find a way to inhibit this enzyme, to keep it from putting any phosphate on tau.

In the laboratory, they purified the enzyme and purified tau protein, and watched tau get phosphorylated by the enzyme. They 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.

They then set up a test of nearly 400 small molecules that fit their criteria. The test results showed three small molecules that can inhibit the enzyme. These are candidates for development as drugs.

Kosik explained 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 that 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
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Source:University of California - Santa Barbara