ON THE FAILURE OF DE NOVO-DESIGNED PEPTIDES AS BIOCATALYSTS

While the elegance and efficiency of enzymatic catalysis have long tem pted chemists and biochemists with reductionist leanings to try to mim ic the functions of natural enzymes in much smaller peptides, such eff orts have only rarely produced catalysts with biologically interesting properties. However, the advent of genetic engineering and hybridoma technology and the discovery of catalytic RNA have led to new and very promising alternative means of biocatalyst development. Synthetic che mists have also had some success in creating nonpeptide catalysts with certain enzyme-like characteristics, although their rates and specifi cities are generally much poorer than those exhibited by the best nove l biocatalysts based on natural structures. A comparison of the variou s approaches from theoretical and practical viewpoints is presented. I t is suggested that, given our curl ent level of understanding, the mo st fruitful methods may incorporate both iterative selection strategie s and rationally chosen small perturbations, superimposed on framework s designed by nature.