Nobel Centennial Symposia
"Frontiers of Molecular Science"

December 4-7, 2001
Friiberghs Manor, Örsundsbro and Stockholm University

Engaging Enzymes in the Synthesis of Their Own Inhibitors

by K. Barry Sharpless
Department of Chemistry and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 N. Torrey Pines Rd. La Jolla, CA 92037, USA

One of our goals in the recent years has been the development of a synthetic approach providing a highly efficient means for generating complex structures from a limited number of specifically designed, reactive components. This strategy, which we termed Click Chemistry, aims at providing a modular and, thence, much quicker access to new, truly diverse libraries of organic compounds for biological testing. However, when used in this way, it still follows the traditional medicinal chemistry approach of making the candidate structures ahead of time, that is before they are presented to the biological system. Engaging the biological system in the synthesis of its own small-molecule inhibitors would be a more productive approach.

Its essence is to provide the biological system of interest with the appropriate reactive modules and allow it to select the best-fitting blocks that will then be ligated, thus synthesizing an inhibitor, in the very heart of the enzyme's catalytic site. Clearly, these reactive modules should be carefully selected in such a way that 1) they have built-in high energy content to drive a spontaneous and irreversible linkage reaction with an appropriate complimentary site in the other block; 2) in the same time, they must be virtually inert towards the chemicals found in biological systems. Organic azides and alkynes clearly meet these criteria, and were therefore chosen to examine this strategy.

Examples of enzymatic systems we have recently investigated using this approach will be discussed in the lecture.