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
|
