Circle Game

Copper-catalyzed azide-alkyne cycloaddition is a reaction that's used to cleanly, rapidly, and irreversibly join a range of substrates by means of 1,2,3-triazole linkages. A Scripps Research Institute team has now determined previously unknown aspects of the reaction's detailed mechanism, such as the fact that two copper centers interact in the course of the process.

The researchers then employed this mechanistic information to develop a potentially important new application of the reaction--its use for head-to-tail dimerization of peptides. Cyclic peptides are of significant interest in biochemical research and drug discovery because they've been found to have promising biological properties. They've been used, for example, to create bioactive nanotubes and in vaccine research.

Assistant professor Valery V. Fokin, associate professor M. G. Finn, and coworkers in Scripps's department of chemistry carried out the mechanistic and synthetic studies [Angew. Chem. Int. Ed., published online Feb. 3, http://www3.interscience. wiley.com/cgi-bin/abstract/109887487 and 109887488]. In the most notable peptide dimerization in their synthetic study, they cyclized two resin-bound 19-amino acid peptide sequences into a 38-residue cyclic peptide, 36 amino acids of which are in the ring.

"This level of ring size, chemical yield, and selectivity is unprecedented," Finn says. "Subsequent unpublished work suggests that the cyclic dimerization process is not limited to peptides but rather is general" for other compound types as well.

Other methods are currently available to carry out peptide cyclodimerizations. However, "I see certain advantages in the azide-alkyne cycloaddition in that it seems to work for larger peptides," says organic chemistry lecturer J. S. Davies of the University of Wales, Swansea. This could come in handy, for example, in efforts to make new peptide vaccines, he says.

A potential drawback of the technique is that the inserted triazole groups could compromise desired biological effects or cause adverse effects in cyclodimerized-peptide drug candidates, Davies notes. Fokin and Finn reply that triazoles are already found in several approved drugs and have been shown to be benign.

"I think that the two papers are extremely important," comments chemistry and biochemistry professor Horst Kessler of the Technical University of Munich. They add a new cycloaddition route to other peptide ligation techniques. "The elucidation of the mechanism and the very easy chemistry provide a nice way to connect chemical entities," he says. The new reaction "could have important implications for the investigation of biologically relevant questions."