Identification of enzyme inhibitors from phage-displayed combinatorial peptide libraries.
In recent years, there have been a growing number of examples of the successful isolation of peptide ligands for enzymes from phage-displayed combinatorial peptide libraries. These peptides typically bind at or near the active site of the enzymes and can inhibit their activity. We review the literature on peptide ligands that have been isolated for enzymes other than proteases as well as present data on peptide ligands we have identified for E. coli dihydrofolate reductase (DHFR) which bind at, or near, the same site as the known inhibitors methotrexate or trimethoprim. Thus, while the peptide ligand isolated from phage-displayed libraries may not resemble the chemical structure of the normal substrate of the enzyme, the peptide can be used as an inhibitor to evaluate the function of the enzyme or for drug discovery efforts (i.e., as a lead compound for peptidomimetic design or as displaceable probe in high-throughput screens of libraries of small molecules).
Kay
B K
BK
Department of Pharmacology, University of Wisconsin-Madison, 1300 University Avenue, Madison, WI 53706-1532, USA. bkkay@facstaff.wisc.edu
Hamilton
P T
PT
D000595:Amino Acid Sequence; D001435:Bacteriophages / Q000187:drug effects / Q000201:enzymology*; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D008024:Ligands; D008969:Molecular Sequence Data; D019151:Peptide Library; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; D019151:Peptide Library; D013762:Tetrahydrofolate Dehydrogenase