Alzheimer's enzyme creates its own inhibitor

Using click chemistry in the fight against brain disease.

A Franco-US team of researchers has made a key Alzheimer’s enzyme create its own inhibitor, which could lead to more efficient drugs for symptomatic treatment of Alzheimer’s disease.

Researchers from the CNRS and the Universit? de la M?diterran?e in Marseille worked with a team of US researchers including Nobel prize winner Barry Sharpless from the Scripps Research Institute in La Jolla, California. They investigated whether click chemistry, a technique pioneered by Sharpless , could be optimised to use enzymes as reaction vessels.

The team chose to use the enzyme acetylcholinesterase (AChE) found in muscle and brain. AChE catalyses the hydrolysis of acetylcholine, a neurotransmitter that mediates muscle contraction and cognitive activities. Many of the drugs used to alleviate the cognitive deficiencies of Alzheimer’s partially inhibit AChE and slow down the breakdown of the neurotransmitter in the brain.

In a cruel bit of chemistry, the researchers used AChE to select the compound that would be most powerful against it. They used the ’gorge’ within the AChE molecule to screen pairs of reactants bearing azide or acetylene groups, knowing that the compounds would link irreversibly to each other in a 1,3-dipolar cycloaddition reaction to form a triazole. At room temperature, this reaction proceeds very slowly and results in regioisomeric anti- and syn- compounds.

One pair of reactants fitted perfectly inside the gorge, where they clicked together rapidly to form a syn1-triazole compound. According to Pascale Marchot of the Marseille team, the two reactants attached to AChE binding sites located at the top and bottom of the gorge and here they were frozen in the perfect positions for fast and selective cycloaddition.

The syn1-triazole compound proved to be a potent inhibitor of AChE. The researchers also claim that it holds AChE in a conformation which has not been observed before, giving the compound promise as a potential drug and helping to explain how AChE works in muscle and brain. The researchers hope that ’the unique structure of the complex captured by click chemistry’ will lead to an unusual strategy for drug design where ’the most selective agents induce distinctive conformational states of the target’.

Dr John Rafferty, a reader in structural biology at the University of Sheffield, predicts that ’the findings may give some critical insights into the mechanism of adhesion by AChE in both normal and disease states. ’Certainly the revelation of alternative binding modes for AChE inhibitors seen here for the syn1 isomer will be of use in further drug design programmes.’

Emma Davies