Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors

• Main Authors: Pehere, Ashok D., Pietsch, Markus, Gütschow, Michael, Neilsen, Paul M., Pedersen, Daniel Sejer, Nguyen, Steven, Zvarec, Ondrej, Sykes, Matthew J., Callen, David F., Abell, Andrew D.
• Other Authors: School of Materials Science & Engineering
• Format: Article
• Language: English
• Published: 2014
• Subjects: DRNTU::Engineering::Materials
• Online Access: https://hdl.handle.net/10356/102746; http://hdl.handle.net/10220/19119
• Institution: Nanyang Technological University

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.