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Some pairs of click chemistry components will fit together
snugly inside the acetylcholinesterase and some will not.
The pairs that do fit snugly together are much more likely
to snap together in the presence of acetylcholinesterase.
In orienting and initiating the reaction, and cutting the
reaction time from years to minutes, the enzyme functions
as a chemical catalyst.
Sharpless calls this variation of click chemistry "in
situ," which is Latin for "in the natural position." In
this case, the reaction is in situ because the enzyme
directs which way the pieces come together. "Once together
in the correct orientation, they will click," he says.
More than the sum of the two parts, the triazole acetylcholinesterase
inhibitor the team found has powerful "femtomolar" " (10-15)
activity against the enzyme. This exceeds by several hundred
times the potency of the hundreds of previously known acetylcholinesterase
"I think it is one of the most fascinating ideas I have
ever heard," says Professor Samuel J. Danishefsky of Memorial
Sloan-Kettering Cancer Center and Columbia University, who
heard Sharpless lecture on this research at Columbia University
about a week after the announcement of his Nobel Prize. "The
very enzyme that you are trying to inhibit was used to assemble
"It works a lot better than we ever anticipated," says Sharpless.
A Simple and Fascinating New Approach
The reaction is an example of what Sharpless calls "click
chemistry," a methodology for chemical synthesis he invented
a few years ago.
"The idea [of click chemistry] is a very simple one," says
TSRI Associate Professor M.G. Finn of the Department of Chemistry
and The Skaggs Institute for Chemical Biology, who is an author
on the report. "If you are going to make a drug (or anything),
why do it with techniques that are difficult when you can
do it with techniques that are easy?"
In click chemistry, chemicals (like acetylcholinesterase
inhibitors) are made from modular chemical "blocks" that can
be joined together in various combinations in very few steps.
Reactions are chosen from readily available starting materials
that react with high reliability and form easily isolated
products in high yield without additional reagents.
Sharpless calls the reactions that join these blocks together
"spring-loaded" because the blocks are designed to have a
higher energy content than the product, which enables them
to react together and form larger structures reliably.
The azides and acetylenes that were used to make the acetylcholinesterase
inhibitors are, according to Sharpless, "cream of the crop"
building blocks for click chemistry, because they will not
react with other molecules but instead fuse irreversibly into
various product structures (triazoles) when brought together.
Selecting the one triazole that is the best inhibitor of
acetylcholinesterase was the job of the acetylcholinesterase
This enzyme has a large binding pocket with separate places
for the azides and acetlyenes to bind. When the two separate
building blocks both bind to the acetylcholinesterase, they
can react and form a triazolethe one that fits best
The best inhibitors thus formed will be those that bind
tighter than the azides and acetylenes from which they are
The research article "Click Chemistry In Situ: Acetylcholinesterase
as a Reaction Vessel for the Selective Assembly of a Femtomolar
Inhibitor from an Array of Building Blocks" is authored by
Warren G. Lewis, Luke G. Green, Flavio Grynszpan, Zoran Radic,
Paul R.Carlier, Palmer Taylor, M.G.Finn, and K. Barry Sharpless
and appears in the March 15, 2002 issue of Angewandte Chemie.
The research was funded by the National Institute for General
Medical Sciences, the National Institutes of Health, the National
Science Foundation, The Skaggs Institute for Chemical Biology,
the W.M. Keck Foundation, and the J.S. Guggenheim Memorial
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