Angewandte Chemie International Edition

Cover image for Vol. 54 Issue 49

Editor: Peter Gölitz, Deputy Editors: Neville Compton, Haymo Ross

Online ISSN: 1521-3773

Associated Title(s): Angewandte Chemie, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemistryOpen, ChemPlusChem, Zeitschrift für Chemie

For full article and contact information, see Angew. Chem. Int. Ed. 2002, 41 (6), 1023 - 1026

No. 6/2002

Enzyme Produces its Own Inhibitor

A new concept for drug research -
researchers develop
a new acetylcholine esterase inhibitor

Even with modern methods, the search for new pharmaceutical agents is a laborious and time-consuming affair. If it were possible to get enzymes and receptors to cooperate actively in the search for their own inhibitors, however, it would make things a little bit easier for researchers. At the Scripps Research Institute in California, researchers have now demonstrated that this thought-experiment actually works in practice.

As a test subject, they selected the enzyme acetylcholine esterase (AChE), which plays an extremely important role in the transmission of nerve impulses. Medications that reversibly inhibit AChE are used in the treatment of Alzheimer’s disease. AChE meets two criteria necessary for the new technique: it has two neighboring binding sites, and small ligand molecules are already known for both of these sites. Starting from two of these inhibitors, tacrin and phenanthridine, a research team working with K. Barry Sharpless, who received the Nobel Prize in chemistry last year, and M. G. Finn wanted to find a new AChE inhibitor; one which would simultaneously bind both sites. This would cause it to bind more tightly, better blocking the enzyme.

The conventional approach to this would be to start by coupling different variations of these two building-blocks in the lab. The resulting compounds would then be brought into contact with the enzyme to determine their effectiveness as inhibitors. Instead, the researchers preferred to equip the various building-block variations with complementary reactive groups. They then exposed pairs of building-blocks to the enzyme, and only in cases where both molecules bound optimally to the enzyme, did they get close enough to react with each other. If a reaction occurred, the resulting compound was guaranteed to be an AChE inhibitor.

The secret to success in this method is the right choice of coupling groups. They must not be so reactive that they couple with each other at room temperature without the enzyme. They must also not attack the enzyme. The American researchers found a solution that is not seen every day. The reactive group of the first building-block is a linear arrangement of three nitrogen atoms, which is attached to a carbon atom. The second building-block contains a triple bond between two carbon atoms. When these two groups are optimally stretched out next to each other, their bonds "flip" around to form a five-membered ring, which fuses the two building-blocks together.

Incidentally, among the 49 possible building-block combinations, only one was a "hit". But it’s not half bad; the resulting compound is by far the strongest reversible AChE inhibitor known to date.