title: Macrocyclic protease inhibitors with reduced peptide character.
abstract: There is a real need for simple structures that define a β-strand conformation, a secondary structure that is central to peptide-protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting β-strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C-terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X-ray crystallography.
authors.affiliation: School of Chemistry & Physics, The University of Adelaide, North Terrace, Adelaide, SA 5005 (Australia).
authors.forename: Krystle C H
authors.initials: KC
authors.lastname: Chua
authors.forename: Markus
authors.initials: M
authors.lastname: Pietsch
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Zhang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hautmann
authors.forename: Hon Y
authors.initials: HY
authors.lastname: Chan
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D001665:Binding Sites; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D057786:Peptidomimetics / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D010455:Peptides; D057786:Peptidomimetics; D011480:Protease Inhibitors
keywords: inhibitors; macrocycles; peptidomimetics; proteases; β-strands