Tricking Diseases into Synthesizing Their Own Worst Enemies:
A Revolutionary Strategy for Drug Discovery Succeeds on an Enzyme

By Jason Socrates Bardi

In a first attempt to test a new general strategy for drug discovery, chemists at The Scripps Research Institute (TSRI) and TSRI's Skaggs Institute for Chemical Biology created the most potent blocking agent known against an enzyme implicated in Alzheimer's disease.

In the March 15 issue of the journal Angewandte Chemie, 2001 Nobel laureate K. Barry Sharpless, W.M. Keck Professor of Chemistry at TSRI, and colleagues at TSRI and the University of California at San Diego, describe how click chemistry, a modular protocol for organic synthesis that Sharpless developed, was used to make a drug-like molecule that powerfully blocks the neurotransmitter destruction caused by the brain enzyme, acetylcholinesterase.

Unlike existing methods, this new drug-discovery strategy—click chemistry—mobilizes the target itself, acetylcholinesterase in this case, to play a decisive role and select the final synthetic step. The acetylcholinesterase enzyme actually catalyzed the click reaction that created that enzyme's own inhibitor, and, remarkably, the result is by far the most potent inhibitor ever discovered for this important, widely studied brain enzyme.

"Think of this as a Trojan Horse approach for battling disease, but this horse goes the Greeks one better," says Sharpless. "We create the pieces that can be clicked together to make the horse, then we leave them outside the gates of, for example, a bacterium. If the pieces look right, it goes to work, constructing its own worst enemy, and doing so within its own defensive walls."

"This is a breakthrough typical of Barry Sharpless," says TSRI President Richard Lerner. "For the first time, you are eliciting a contribution from the dynamic enzyme, asking it to make the inhibitor it prefers."

Troy's Homemade Horse

Finding inhibitors, molecules that fit snuggly into the active sites of a particular target and modulate its activities, is the basis for molecular medicine. Essentially all diseases operate by inducing unnatural function in enzymes. Many of those diseases, including cancer, not to mention a whole alphabet of ailments starting with AIDS, Alzheimer's, anthrax, and arthritis, can be treated by inhibiting enzymes.

The enzyme selected for click chemistry's proof-in-practice was one of the first brain enzymes to be identified. Acetylchonlinesterase breaks down acetylcholine, the neurotransmitter that propagates nerve signals. Inhibitors of acetylcholinesterase are used to treat the dementia associated with Alzheimer's disease, increasing the amount of acetylcholine in the brain, in turn enhancing brain activity.

In the current study, Sharpless and his team synthesized specialized molecules, which are stable as they are but which also possess a built-in programmed desire to be incorporated whole into a larger molecule. When several such components in this molecular construction set are brought together in specific ensembles, their pre-programming causes them to react by cycloaddition, predictably and irreversibly clicking together to create a single larger molecule with no by-products.

Under normal circumstances, with the click chemistry components randomly circulating in a reaction vessel, it might take years to line up properly for a click reaction to take place. However, when the target enzyme was introduced into the picture, active spots on the enzyme's surface acted like hands that grabbed and oriented the click components, snapping them together.



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"Think of this as a Trojan Horse approach for battling disease, but this horse goes the Greeks one better."

—K. Barry Sharpless