The cover picture shows the electric eel, Electrophorus electricus, a source for commercially available acetylcholinesterase. In an experiment described by K. B. Sharpless and M. G. Finn and co‐workers on pp. 1053–1057, a femtomolar inhibitor was assembled by the enzyme from a collection of building blocks containing azide and alkyne functional groups, shown floating in solution. The templated 1,3‐dipolar cycloaddition reaction, producing the inhibitor, is represented by the flare of light at the center of the image.

Form‐fitting chemistry in a protein mold is enabled by the use of the 1,3‐dipolar cycloaddition of azides and alkynes. The enzyme acetylcholinesterase preferentially assembles one pair of these reactants, each of which bears a group that binds to adjacent positions on the protein structure (see picture), into a 1,2,3‐triazole adduct that is the most potent noncovalent inhibitor of the enzyme yet developed.

The generation and/or optimization of lead compounds by combinatorial methods has become widely accepted in medicinal chemistry, and is the subject of continued improvement. [1±3] However, most combinatorial strategies remain dependent upon iterative cycles of synthesis and screening. The direct involvement of the target, usually a receptor or enzyme, in the selection, evolution, and screening of drug candidates can accelerate the discovery process by shortcircuiting its traditionally stepwise nature. [4±11] The use of an enzyme target to select building blocks and synthesize its own inhibitor is a relatively unexplored option. This approach depends on the simultaneous binding of two ligands, decorated with complementary reactive groups, to adjacent sites on the protein; their co-localization is then likely to accelerate the reaction that connects them. [12] When the catalysis of such bond formation is blocked by product inhibition, the higher affinity products [12±14] then serve as lead compounds. This and similar approaches that have been adopted by a number of investigators employ one of five types[*] Prof.

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The first successful sol−gel entrapment of monoclonal catalytic antibodies is described. Antibodies which catalyze various hydrolytic reactions were entrapped directly in a tetramethoxysilane-derived silica sol−gel matrix, retaining their activity. The catalytic reactions were carried out either batchwise or in a continuous flow apparatus, demonstrating the utility of these novel biocatalysts for preparative scale organic synthesis.