An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity.

Autor: Lemke C; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany., Benýšek J; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic.; First Faculty of Medicine, Charles University, Kateřinská 32, Prague 12108, Czech Republic., Brajtenbach D; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany., Breuer C; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.; Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, Rheinbach 53359, Germany., Jílková A; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic., Horn M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic., Buša M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic.; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, Prague 12800, Czech Republic., Ulrychová L; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic., Illies A; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany., Kubatzky KF; Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Im Neuenheimer Feld 324, Heidelberg 69120, Germany., Bartz U; Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, Rheinbach 53359, Germany., Mareš M; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic., Gütschow M; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2021 Sep 23; Vol. 64 (18), pp. 13793-13806. Date of Electronic Publication: 2021 Sep 02.
DOI: 10.1021/acs.jmedchem.1c01178
Abstrakt: 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 ( k inac / K i = 35,300 M -1 s -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: MEDLINE
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