An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity
| Autor: | Lenka Ulrychová, Martin Horn, Carina Lemke, Michal Buša, Michael Gütschow, Dominik Brajtenbach, Jakub Benýšek, Christian Breuer, Katharina F. Kubatzky, Annika Illies, Adéla Jílková, Ulrike Bartz, Michael Mareš |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cathepsin
Acrylamides Microscopy Confocal Chemistry Cathepsin K Cysteine Proteinase Inhibitors Cysteine protease Fluorescence Microscopy Fluorescence Biochemistry Live cell imaging Catalytic Domain Cell Line Tumor Drug Design Drug Discovery Proteome Humans Molecular Medicine Moiety Selectivity Fluorescent Dyes Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 64:13793-13806 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01178 |
| Popis: | The cysteine protease cathepsin K is a target for the treatment of diseases associated with high bone turnover. Cathepsin K is mainly expressed in osteoclasts and responsible for the destruction of the proteinaceous components of the bone matrix. We designed various fluorescent activity-based probes (ABPs) and their precursors that bind to and inactivate cathepsin K. ABP 25 exhibited extraordinary potency (kinac/Ki = 35,300 M-1s-1) and selectivity for human cathepsin K. Crystal structures of cathepsin K in complex with ABP 25 and its nonfluorescent precursor 21 were determined to characterize the binding mode of this new type of acrylamide-based Michael acceptor with the particular orientation of the dibenzylamine moiety to the primed subsite region. The cyanine-5 containing probe 25 allowed for sensitive detection of cathepsin K, selective visualization in complex proteomes, and live cell imaging of a human osteosarcoma cell line, underlining its applicability in a pathophysiological environment. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|