Bicyclic peptide inhibitor reveals large contact interface with a protease target

ACS Chem Biol. 2012 May 18;7(5):817-21. doi: 10.1021/cb200478t. Epub 2012 Feb 15.


From a large combinatorial library of chemically constrained bicyclic peptides we isolated a selective and potent (K(i) = 53 nM) inhibitor of human urokinase-type plasminogen activator (uPA) and crystallized the complex. This revealed an extended structure of the peptide with both peptide loops engaging the target to form a large interaction surface of 701 Å(2) with multiple hydrogen bonds and complementary charge interactions, explaining the high affinity and specificity of the inhibitor. The interface resembles that between two proteins and suggests that these constrained peptides have the potential to act as small protein mimics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Bridged Bicyclo Compounds / chemistry*
  • Bridged Bicyclo Compounds / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Protein Binding
  • Urokinase-Type Plasminogen Activator / antagonists & inhibitors*
  • Urokinase-Type Plasminogen Activator / chemistry
  • Urokinase-Type Plasminogen Activator / metabolism


  • Bridged Bicyclo Compounds
  • Enzyme Inhibitors
  • Peptides
  • Urokinase-Type Plasminogen Activator