Identification of enzyme inhibitors from phage-displayed combinatorial peptide libraries

In recent years, there have been a growing number of examples of the succes sful isolation of peptide ligands for enzymes from phage-displayed combinat orial peptide libraries. These peptides typically bind at or near the activ e site of the enzymes and can inhibit their activity. We review the literat ure on peptide ligands that have been isolated for enzymes other than prote ases as well as present data on peptide ligands we have identified for E. c oli dihydrofolate reductase (DHFR) which bind at, or near, the same site as the known inhibitors methotrexate or trimethoprim. Thus, while the peptide li.-and isolated from phage-displayed libraries may not resemble the chemi cal structure of the normal substrate of the enzyme, the peptide can be use d as an inhibitor to evaluate the function of the enzyme or for drug discov ery efforts (i.e,, as a lead compound for peptidomimetic design or as displ aceable probe in high-throughput screens of libraries of small molecules).