Bicyclic Peptide Inhibitor Reveals Large Contact Interface with a Protease Target

• DOI: 10.1021/cb200478t
• Publication Date: 2012-02-03T21:16:31Z
• Authors: Alessandro Angelini; Laura Cendron; Shiyu Chen; Jeremy Touati; Greg Winter; Giuseppe Zanotti; Christian Heinis
• Keywords: Models, Molecular; 0301 basic medicine; 0303 health sciences; Binding Sites; Molecular Sequence Data; Hydrogen Bonding; Urokinase-Type Plasminogen Activator; Bridged Bicyclo Compounds; 03 medical and health sciences; Humans; Amino Acid Sequence; Enzyme Inhibitors; Peptides; Protein Binding

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.