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An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity
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...
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Published in: | Journal of medicinal chemistry 2021-09, Vol.64 (18), p.13793-13806 |
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container_title | Journal of medicinal chemistry |
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creator | Lemke, Carina Benýšek, Jakub Brajtenbach, Dominik Breuer, Christian Jílková, Adéla Horn, Martin Buša, Michal Ulrychová, Lenka Illies, Annika Kubatzky, Katharina F Bartz, Ulrike Mareš, Michael Gütschow, Michael |
description | 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–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. |
doi_str_mv | 10.1021/acs.jmedchem.1c01178 |
format | article |
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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–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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01178</identifier><identifier>PMID: 34473502</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acrylamides - chemical synthesis ; Acrylamides - chemistry ; Acrylamides - metabolism ; Catalytic Domain ; Cathepsin K - antagonists & inhibitors ; Cathepsin K - chemistry ; Cathepsin K - metabolism ; Cell Line, Tumor ; Cysteine Proteinase Inhibitors - chemical synthesis ; Cysteine Proteinase Inhibitors - chemistry ; Cysteine Proteinase Inhibitors - metabolism ; Drug Design ; Fluorescent Dyes - chemical synthesis ; Fluorescent Dyes - chemistry ; Fluorescent Dyes - metabolism ; Humans ; Microscopy, Confocal ; Microscopy, Fluorescence ; Protein Binding</subject><ispartof>Journal of medicinal chemistry, 2021-09, Vol.64 (18), p.13793-13806</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-da888264100f1808836ab94554a6fda214fd427b54ae07dd4d73e0ef2e2fd7563</citedby><cites>FETCH-LOGICAL-a348t-da888264100f1808836ab94554a6fda214fd427b54ae07dd4d73e0ef2e2fd7563</cites><orcidid>0000-0002-9376-7897 ; 0000-0001-9110-2018 ; 0000-0002-0847-5022</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34473502$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lemke, Carina</creatorcontrib><creatorcontrib>Benýšek, Jakub</creatorcontrib><creatorcontrib>Brajtenbach, Dominik</creatorcontrib><creatorcontrib>Breuer, Christian</creatorcontrib><creatorcontrib>Jílková, Adéla</creatorcontrib><creatorcontrib>Horn, Martin</creatorcontrib><creatorcontrib>Buša, Michal</creatorcontrib><creatorcontrib>Ulrychová, Lenka</creatorcontrib><creatorcontrib>Illies, Annika</creatorcontrib><creatorcontrib>Kubatzky, Katharina F</creatorcontrib><creatorcontrib>Bartz, Ulrike</creatorcontrib><creatorcontrib>Mareš, Michael</creatorcontrib><creatorcontrib>Gütschow, Michael</creatorcontrib><title>An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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–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.</description><subject>Acrylamides - chemical synthesis</subject><subject>Acrylamides - chemistry</subject><subject>Acrylamides - metabolism</subject><subject>Catalytic Domain</subject><subject>Cathepsin K - antagonists & inhibitors</subject><subject>Cathepsin K - chemistry</subject><subject>Cathepsin K - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cysteine Proteinase Inhibitors - chemical synthesis</subject><subject>Cysteine Proteinase Inhibitors - chemistry</subject><subject>Cysteine Proteinase Inhibitors - metabolism</subject><subject>Drug Design</subject><subject>Fluorescent Dyes - chemical synthesis</subject><subject>Fluorescent Dyes - chemistry</subject><subject>Fluorescent Dyes - metabolism</subject><subject>Humans</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Fluorescence</subject><subject>Protein Binding</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kFtPwkAQhTdGI4j-A2P20Zfi7KXt8ogElUgiiZfXzdKdhZJesNuq_HuLVB99mkzmnDMzHyGXDIYMOLsxiR9ucrTJGvMhS4CxWB2RPgs5BFKBPCZ9AM4DHnHRI2febwBAMC5OSU9IGYsQeJ-8jQs6Tur0I613wa3xaOmiKpdIXVnRianXuPVpQR_pLDertFjRz7Re0-lXglmGRU0XZY1FsqOmsPQZM-yizsmJM5nHi64OyOvd9GXyEMyf7meT8TwwQqo6sEYpxSPJABxToJSIzHIkw1CayFnDmXRW8njZ9gixtdLGAgEdR-5sHEZiQK4PuduqfG_Q1zpP_f42U2DZeM3DaCTiSI54K5UHaVKV3lfo9LZKc1PtNAO9J6pbovqXqO6ItrarbkOzbGd_pl-ErQAOgh972VRF-_D_md-hboTB</recordid><startdate>20210923</startdate><enddate>20210923</enddate><creator>Lemke, Carina</creator><creator>Benýšek, Jakub</creator><creator>Brajtenbach, Dominik</creator><creator>Breuer, Christian</creator><creator>Jílková, Adéla</creator><creator>Horn, Martin</creator><creator>Buša, Michal</creator><creator>Ulrychová, Lenka</creator><creator>Illies, Annika</creator><creator>Kubatzky, Katharina F</creator><creator>Bartz, Ulrike</creator><creator>Mareš, Michael</creator><creator>Gütschow, Michael</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-9376-7897</orcidid><orcidid>https://orcid.org/0000-0001-9110-2018</orcidid><orcidid>https://orcid.org/0000-0002-0847-5022</orcidid></search><sort><creationdate>20210923</creationdate><title>An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity</title><author>Lemke, Carina ; Benýšek, Jakub ; Brajtenbach, Dominik ; Breuer, Christian ; Jílková, Adéla ; Horn, Martin ; Buša, Michal ; Ulrychová, Lenka ; Illies, Annika ; Kubatzky, Katharina F ; Bartz, Ulrike ; Mareš, Michael ; Gütschow, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-da888264100f1808836ab94554a6fda214fd427b54ae07dd4d73e0ef2e2fd7563</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acrylamides - chemical synthesis</topic><topic>Acrylamides - chemistry</topic><topic>Acrylamides - metabolism</topic><topic>Catalytic Domain</topic><topic>Cathepsin K - antagonists & inhibitors</topic><topic>Cathepsin K - chemistry</topic><topic>Cathepsin K - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cysteine Proteinase Inhibitors - chemical synthesis</topic><topic>Cysteine Proteinase Inhibitors - chemistry</topic><topic>Cysteine Proteinase Inhibitors - metabolism</topic><topic>Drug Design</topic><topic>Fluorescent Dyes - chemical synthesis</topic><topic>Fluorescent Dyes - chemistry</topic><topic>Fluorescent Dyes - metabolism</topic><topic>Humans</topic><topic>Microscopy, Confocal</topic><topic>Microscopy, Fluorescence</topic><topic>Protein Binding</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lemke, Carina</creatorcontrib><creatorcontrib>Benýšek, Jakub</creatorcontrib><creatorcontrib>Brajtenbach, Dominik</creatorcontrib><creatorcontrib>Breuer, Christian</creatorcontrib><creatorcontrib>Jílková, Adéla</creatorcontrib><creatorcontrib>Horn, Martin</creatorcontrib><creatorcontrib>Buša, Michal</creatorcontrib><creatorcontrib>Ulrychová, Lenka</creatorcontrib><creatorcontrib>Illies, Annika</creatorcontrib><creatorcontrib>Kubatzky, Katharina F</creatorcontrib><creatorcontrib>Bartz, Ulrike</creatorcontrib><creatorcontrib>Mareš, Michael</creatorcontrib><creatorcontrib>Gütschow, Michael</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lemke, Carina</au><au>Benýšek, Jakub</au><au>Brajtenbach, Dominik</au><au>Breuer, Christian</au><au>Jílková, Adéla</au><au>Horn, Martin</au><au>Buša, Michal</au><au>Ulrychová, Lenka</au><au>Illies, Annika</au><au>Kubatzky, Katharina F</au><au>Bartz, Ulrike</au><au>Mareš, Michael</au><au>Gütschow, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2021-09-23</date><risdate>2021</risdate><volume>64</volume><issue>18</issue><spage>13793</spage><epage>13806</epage><pages>13793-13806</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>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–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. 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subjects | Acrylamides - chemical synthesis Acrylamides - chemistry Acrylamides - metabolism Catalytic Domain Cathepsin K - antagonists & inhibitors Cathepsin K - chemistry Cathepsin K - metabolism Cell Line, Tumor Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - chemistry Cysteine Proteinase Inhibitors - metabolism Drug Design Fluorescent Dyes - chemical synthesis Fluorescent Dyes - chemistry Fluorescent Dyes - metabolism Humans Microscopy, Confocal Microscopy, Fluorescence Protein Binding |
title | An Activity-Based Probe for Cathepsin K Imaging with Excellent Potency and Selectivity |
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