A Modular Assembly Strategy for Improving the Substrate Specificity of Small Catalytic Peptides

Substrate specificity is one of the hallmarks of enzymes. Substrate specificity allows an enzyme to catalyze a reaction involving substrate molecules found within a complex mixture of compounds possessing the same functional groups. Generation of designer protein catalysts that possess substrate specificity has been dem-onstrated by modification of Nature’s enzymes1 and by the preparation of catalytic antibodies.2 In contrast to large proteins, small peptide catalysts have demonstrated limited specificity for small-molecule substrates.3 This is presumably a result of the limited opportunities small peptides have to fold in a manner that provides for the formation of an isolated reaction vessel that effectively binds and sequesters substrates from bulk solvent while at the same time catalyzing their transformation. To explore routes for the preparation of small peptide enzymes that possess improved substrate specific-ity, we have examined a modular assembly strategy. Here w