title: An inhibitor of sequence-specific proteolysis that targets the substrate rather than the enzyme.
abstract: BACKGROUND
  Traditional protease inhibitors target the active site of the enzyme. However, since most proteases act on multiple substrates, even the most specific protease inhibitors will affect the levels of a number of different proteins. However, if substrate-targeted inhibitors could be developed, much higher levels of specificity could be achieved. In theory, compounds that bind the cleavage site of a particular substrate could block its interaction with a protease without having any effect on the processing of other substrates of that protease.
  
  
  RESULTS
  A model system is presented that demonstrates the feasibility of substrate-targeted inhibition of proteolysis. A peptide selected genetically to bind a 14-residue epitope that encompasses the cleavage site of human pro-IL-1beta was shown to inhibit interleukin-converting enzyme (ICE)-mediated proteolysis of model substrates containing the 14-mer target sequence. However, the peptide had no effect on the cleavage of other ICE substrates with different amino acids flanking the minimal cleavage site.
  
  
  CONCLUSIONS
  This study demonstrates the feasibility of substrate-targeted inhibition of proteolysis. More potent compounds must be developed before substrate-targeted inhibitors can be used routinely. Nonetheless, this novel strategy for protease inhibition seems promising for the development of extremely selective molecules with which to manipulate the maturation of many important pro-hormones, -cytokines and -proteins.
authors.affiliation: Center for Biomedical Inventions, Department of Internal Medicine and Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8573, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Ly
authors.forename: T
authors.initials: T
authors.lastname: Kodadek
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D015195:Drug Design; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D010455:Peptides; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; D010450:Endopeptidases; D020170:Caspase 1