Chemists trick Alzheimer's enzyme

LA JOLLA, Calif., March 15 (UPI) -- Chemists at the Scripps Research Institute in La Jolla said Friday they have tricked an enzyme essential in Alzheimer's disease into blocking its own debilitating action.

A team led by Nobel laureate K. Barry Sharpless developed the chemical trick, called "click chemistry," to make a molecule that blocks neurotransmitter destruction caused by the brain enzyme acetylcholinesterase.

The destructive enzyme catalyzes the so-called "click reaction" that creates its own worst enemy -- its most potent inhibitor.

"Think of this as a Trojan Horse approach for battling disease, but this horse goes the Greeks one better," Sharpless, W.M. Keck professor of chemistry at Scripps, said in a prepared statement. "We create the pieces that can be clicked together to make the horse."

Once the disease-causing enzyme assembles the horse, Sharpless explained, out march the inhibitors, chemical soldiers who stop the enzyme cold. By assembling its own inhibitor, the enzyme actually designs the drug that will best halts its progress.

"This is indeed a revolutionary method in rational drug design," neuroscientist James Olds, director of the Krasnow Institute for Neurobiology at George Mason University in Fairfax, Va., told United Press International. "It may have great applicability to improving the specificity of drugs, particularly those currently used in the treatment of neurological and psychiatric diseases."

Molecular drug designers make inhibitor molecules that fit snuggly into the active sites of target enzymes, blocking their action on other molecules. Many diseases -- cancer, AIDS, Alzheimer's, arthritis and anthrax, for instance -- induce unnatural functions in enzymes. Inhibiting enzyme action can treat these diseases.

Enzyme active sites are also highly specific, so drugs react only with the sites and nowhere else.

"A major problem of current drugs is that they are 'dirty', that is, they have side effects -- often untoward -- because they interact with proteins or enzymes other than the ones planned for," Olds, an expert on neurological diseases, told UPI.

"In addition, Sharpless' method may have great import in designing drugs to interact

with proteins for which we presently have no good compounds," he said.

The enzyme selected for the click chemistry test, acetylchonlinesterase, was one of

the first brain enzymes identified. It breaks down acetylcholine, the neurotransmitter that propagates nerve signals. Inhibitors of acetylcholinesterase treat the dementia associated with Alzheimer's disease by increasing the amount of acetylcholine in the brain.

Sharpless and his team synthesized molecular building blocks that, when pieced together, create a single larger molecule with no by-products -- an acetylcholinesterase inhibitor. With the blocks in place, the essential ingredient -- the enemy enzyme itself -- goes to

work. The trick -- active spots on the acetylcholinesterase surface act like hands that grab and orient the click components of the inhibitor, snapping them together.

"The building blocks react only with each other, and not with anything else in the mixture," Scripps Research Institute chemistry professor and study co-author M.G. Finn told UPI from La Jolla.

"Furthermore, the reaction occurs only when the pieces are held by the target enzyme -- acetylcholinesterase -- next to each other, not when they happen to bump into each other in solution."

In other words, the disease-causing enzyme welds the bars of its own prison.

(Reported by UPI Science Correspondent Mike Martin in Columbia, Mo.)