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click chemistry to discover potent new inhibitors of
acetylcholinesterase, an enzyme that serves as a drug target in
Alzheimer's disease, writes Phil Taylor.
Click chemistry, or in situ click chemistry to give it its full name, involves using a molecule as a template to bring together a series of molecular building blocks, which 'click' together much like Lego pieces and end up forming an inhibitor of the original molecule. Put simply, the molecule itself acts as a catalyst in a synthetic reaction which creates its own highly-potent and specific inhibitor.
While the concept is not new, the researchers, from the European Institute of Chemistry & Biology in Bordeaux, France, the Scripps Research Institute and the University of California San Diego in the US believe they are the first to apply it systematically on a large-scale to the design of new drugs.
Using this approach, the researchers used acetylcholinesterase (AChE) as a microscopic reaction vessel to make potent inhibitors of the enzyme. A number of AChE inhibitors - including Pfizer and Eisai's Aricept (donepezil) and Novartis' Exelon (rivastigmine) - are already in use to treat Alzheimer's disease. But while these have proven effects on cognition and memory in mild Alzheimer's, their ability to affect the course of the disease has been disappointing and their use has been somewhat limited by side effects.
The scientists believe that their new process - which differs from prior approaches in that it uses a particular type of chemistry (cycloaddition) to ensure that the building blocks only join together when they are in very close proximity - offers the potential for development of more potent drugs with fewer side effects.
Published in a recent issue of Proceedings of the National Academy of Science, the study revealed that the formation of the inhibitor on the enzyme template using click chemistry proceeds about a million times more rapidly than under typical laboratory conditions in test tubes.
"The enzyme template is a fluctuating structure with many inherent conformations," said Palmer Taylor, one of the study's authors.
While the compounds formed by click chemistry have high affinity for their targets, the real potential lies in the selectivity of the inhibitor formed on the target surface for one of the many closely related enzymes or drug receptors, he added.
The elegance of the approach is that it does not rely on characterising the function of a molecule in the presence of a drug candidate, but rather on detecting the production of a new small molecular structure. And it should be simple to extend the approach away from enzymes and into other protein classes.
Moreover, the same reaction can be used to synthesise sufficient quantities of the small-molecule inhibitor in a fairly cheap way in order to allow preliminary testing.
