title: Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors.
abstract: Peptide-derived protease inhibitors are an important class of compounds with the potential to treat a wide range of diseases. Herein, we describe the synthesis of a series of triazole-containing macrocyclic protease inhibitors pre-organized into a β-strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azido-alkyne-based aldehydes are also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards calpain II, cathepsin L and S, and the 20S proteasome chymotrypsin-like activity. Some of the first examples of highly potent macrocyclic inhibitors of cathepsin S were identified. These adopt a well-defined β-strand geometry as shown by NMR spectroscopy, X-ray analysis, and molecular docking studies.
authors.affiliation: School of Chemistry & Physics, The University of Adelaide, North Terrace, Adelaide, SA 5005, Australia.
authors.forename: Ashok D
authors.initials: AD
authors.lastname: Pehere
authors.forename: Markus
authors.initials: M
authors.lastname: Pietsch
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Paul M
authors.initials: PM
authors.lastname: Neilsen
authors.forename: Daniel Sejer
authors.initials: DS
authors.lastname: Pedersen
authors.forename: Steven
authors.initials: S
authors.lastname: Nguyen
authors.forename: Ondrej
authors.initials: O
authors.lastname: Zvarec
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sykes
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
mesh_terms: D002154:Calpain / Q000037:antagonists & inhibitors; D056668:Cathepsin L / Q000037:antagonists & inhibitors; D057930:Click Chemistry; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D057786:Peptidomimetics; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047028:Macrocyclic Compounds; D010455:Peptides; D057786:Peptidomimetics; D011480:Protease Inhibitors; D014230:Triazoles; D002154:Calpain; D056668:Cathepsin L; D046988:Proteasome Endopeptidase Complex