Click and Clack

A new paper describes how combining fragment classes that selectively react with each other can yield an inhibitor to a protein-protein interaction.

Most of you are probably familiar with the concept of “click chemistry”, exemplified by the Huisgen cycloaddition of azides and acetylenes to form triazoles, and defined earlier this century by K. Barry Sharpless and colleagues. The idea, put very simply, is to react two molecules selectively and reliably to generate a product in high yield. The approach has obvious applications to fragment-based ligand discovery, and in fact Sharpless and co-workers demonstrated that the enzyme acetylcholinesterase can catalyze the formation of an inhibitor with femtomolar potency, starting from two fairly large and potent “fragments,” one containing an azide, the other an alkyne.

The notion of using a protein as a template on which to assemble an inhibitor dates back further than click chemistry. Huc and Lehn used reductive amination between aldehydes and amines in the presence of carbonic anhydrase to capture molecules that interacted more strongly with the protein than did the starting materials, and the technology even formed the basis of a company, Therascope.

In the latest example of this line of research, Roman Manetsch and colleagues find that the antiapoptotic cancer target Bcl-xL is able to catalyze the formation of an inhibitor from fragments sporting thioacids and sulfonyl azides; the inhibitor itself was previously discovered using different fragment-based methods at Abbott. The reaction appears to be relatively fast, and works even in the presence of a small pool of sulfonyl azides.


The paper, published this month in the Journal of the American Chemical Society, is a nice proof-of-concept study, but it does raise practical questions. First, the authors report the use of only six sulfonyl azides and three thioacids. These generally need to be custom-made rather than purchased; how much of a barrier will this represent to other practitioners? Once assembled, how stable will these fragments be in long-term storage? Finally, the product acylsulfonamide is a rather special entity not commonly found in drugs, and with a limited range of bioisosteres (indeed, it was originally employed at Abbott to replace a carboxylic acid). Still, the paper does provide an interesting - if less conventional - method of fragment-based lead discovery.