Recent efforts to control amyloid-, a protein with a suspected major role in causing Alzheimer’s disease (AD), include various approaches. Vaccines and gene therapy are two directions being investigated. Now protein binding has been announced as a different method of attacking the problem, and basic research is being carried out in this direction.

Receptor design. The ion pairing and hydrogen bonds make the receptor–substrate interaction strong enough for the supramolecular complex to prevail even under aqueous conditions. The side chains can be adjusted for particular protein targets.

Carsten Schmuck, from the University of Cologne (Germany), and Ulrich E. Hackler, from Chemspeed Ltd. (Switzerland) believe that gaining a deeper insight into molecular recognition is necessary for a better understanding of diseases such as AD, in which self-aggregation of peptide fragments plays an important role. Hackler presented their findings at the Drug Discovery Japan Conference in Tokyo in March. “Our focus is on model compounds that help us to understand, in a thermodynamic and kinetic sense, the very difficult noncovalent interactions that are the basis on which all proteins function,” says Hackler.

Even in highly polar solvents, 2-(guanidiniocarbonyl)-1H-pyrroles bind carboxylates by ion pairing in combination with multiple hydrogen bonds. Therefore, they can be used as receptors for stereoselective complexes of amino acid and small peptide carboxylates in aqueous solvents.

The team prepared 24 different receptors by coupling a parent guanidiniocarbonyl-pyrrole-carboxylate zwitterion with various amines using automated, parallel synthesis. The selective side-chain interactions that occur allow researchers to fine-tune the affinity of the receptor to certain targets. The targets can be simple amino acids or oligopeptides, Hackler explained. “Depending on the amino acid sequence of that oligopeptide, you can make the receptor susceptible to a certain protein. Since this receptor binds the free C-terminus of any given protein, we are now working on a suitable side chain to give a favorable interaction between our receptor and the amyloid protein that is responsible for forming the plaques, which in turn are responsible for AD.”

Tempered enthusiasm greeted the talk. “The compound is a long way off [from] being a selective -amyloid binder,” said Andrew M. Bray of Mimotopes Pty. Ltd. (Victoria, Australia). “But molecular recognition is an area where each step has to be taken in order to get to the next step.”

Next year, Hackler’s team hopes to demonstrate a receptor that can identify the AD protein. However, Hackler thinks that a real drug is 15 years away. “We still have a lot of work to do in fine-tuning the receptor side chain,” he says.