An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Acrylamides chemical synthesis chemistry metabolism MeSH
- Fluorescent Dyes chemical synthesis chemistry metabolism MeSH
- Microscopy, Fluorescence MeSH
- Cysteine Proteinase Inhibitors chemical synthesis chemistry metabolism MeSH
- Catalytic Domain MeSH
- Cathepsin K antagonists & inhibitors chemistry metabolism MeSH
- Microscopy, Confocal MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Drug Design MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acrylamides MeSH
- CTSK protein, human MeSH Browser
- Fluorescent Dyes MeSH
- Cysteine Proteinase Inhibitors MeSH
- Cathepsin K MeSH
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.
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