Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β
ABSTRACT Zinc metalloproteinases meprin α and meprin β are implicated in a variety of diseases, such as fibrosis, inflammation and neurodegeneration, however, there are no selective small molecule inhibitors that would allow to study their role in these processes. To address this lack of molecular t...
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| Veröffentlicht in: | Biopolymers 2014-09, Vol.102 (5), p.396-406 |
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| creator | Madoux, Franck Tredup, Claudia Spicer, Timothy P. Scampavia, Louis Chase, Peter S. Hodder, Peter S. Fields, Gregg B. Becker-Pauly, Christoph Minond, Dmitriy |
| description | ABSTRACT
Zinc metalloproteinases meprin α and meprin β are implicated in a variety of diseases, such as fibrosis, inflammation and neurodegeneration, however, there are no selective small molecule inhibitors that would allow to study their role in these processes. To address this lack of molecular tools, we have developed high throughput screening assays to enable discovery of inhibitors of both meprin α and meprin β and screened a collection of well characterized pharmaceutical agents (library of pharmaceutically active compounds, n = 1,280 compounds). Two compounds (PPNDS, NF449) confirmed their activity and selectivity for meprin β. Kinetic studies revealed competitive (PPNDS) and mixed competitive/noncompetitive (NF449) inhibition mechanisms suggesting that binding occurs in meprin β active site. Both PPNDS and NF449 exhibited low nanomolar IC50 and Ki values making them the most potent and selective inhibitors of meprin β reported to the date. These results demonstrate the ability of meprin α and β assays to identify selective compounds and discard artifacts of primary screening. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 396–406, 2014. |
| doi_str_mv | 10.1002/bip.22527 |
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Zinc metalloproteinases meprin α and meprin β are implicated in a variety of diseases, such as fibrosis, inflammation and neurodegeneration, however, there are no selective small molecule inhibitors that would allow to study their role in these processes. To address this lack of molecular tools, we have developed high throughput screening assays to enable discovery of inhibitors of both meprin α and meprin β and screened a collection of well characterized pharmaceutical agents (library of pharmaceutically active compounds, n = 1,280 compounds). Two compounds (PPNDS, NF449) confirmed their activity and selectivity for meprin β. Kinetic studies revealed competitive (PPNDS) and mixed competitive/noncompetitive (NF449) inhibition mechanisms suggesting that binding occurs in meprin β active site. Both PPNDS and NF449 exhibited low nanomolar IC50 and Ki values making them the most potent and selective inhibitors of meprin β reported to the date. These results demonstrate the ability of meprin α and β assays to identify selective compounds and discard artifacts of primary screening. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 396–406, 2014.</description><identifier>ISSN: 0006-3525</identifier><identifier>EISSN: 1097-0282</identifier><identifier>DOI: 10.1002/bip.22527</identifier><identifier>PMID: 25048711</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>actinonin ; Assaying ; Binding ; Biological Assay ; Biopolymers ; Databases, Chemical ; Fibrosis ; High-Throughput Screening Assays - methods ; HTS ; Humans ; Inhibitors ; Matrix Metalloproteinase Inhibitors - analysis ; Matrix Metalloproteinase Inhibitors - pharmacology ; meprin ; Metalloendopeptidases - antagonists & inhibitors ; Metalloendopeptidases - chemistry ; NF449 ; Pilot Projects ; Pilots ; PPNDS ; Reproducibility of Results ; Screening ; Substrate Specificity - drug effects ; suramin ; Time Factors ; Zinc ; zinc metalloproteinase</subject><ispartof>Biopolymers, 2014-09, Vol.102 (5), p.396-406</ispartof><rights>2014 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4647-14a5862c51443e18c8f66837aeb8756f8988b8601d2621f16c1e0baab36712b93</citedby><cites>FETCH-LOGICAL-c4647-14a5862c51443e18c8f66837aeb8756f8988b8601d2621f16c1e0baab36712b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fbip.22527$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fbip.22527$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25048711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Madoux, Franck</creatorcontrib><creatorcontrib>Tredup, Claudia</creatorcontrib><creatorcontrib>Spicer, Timothy P.</creatorcontrib><creatorcontrib>Scampavia, Louis</creatorcontrib><creatorcontrib>Chase, Peter S.</creatorcontrib><creatorcontrib>Hodder, Peter S.</creatorcontrib><creatorcontrib>Fields, Gregg B.</creatorcontrib><creatorcontrib>Becker-Pauly, Christoph</creatorcontrib><creatorcontrib>Minond, Dmitriy</creatorcontrib><title>Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β</title><title>Biopolymers</title><addtitle>Biopolymers</addtitle><description>ABSTRACT
Zinc metalloproteinases meprin α and meprin β are implicated in a variety of diseases, such as fibrosis, inflammation and neurodegeneration, however, there are no selective small molecule inhibitors that would allow to study their role in these processes. To address this lack of molecular tools, we have developed high throughput screening assays to enable discovery of inhibitors of both meprin α and meprin β and screened a collection of well characterized pharmaceutical agents (library of pharmaceutically active compounds, n = 1,280 compounds). Two compounds (PPNDS, NF449) confirmed their activity and selectivity for meprin β. Kinetic studies revealed competitive (PPNDS) and mixed competitive/noncompetitive (NF449) inhibition mechanisms suggesting that binding occurs in meprin β active site. Both PPNDS and NF449 exhibited low nanomolar IC50 and Ki values making them the most potent and selective inhibitors of meprin β reported to the date. These results demonstrate the ability of meprin α and β assays to identify selective compounds and discard artifacts of primary screening. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 396–406, 2014.</description><subject>actinonin</subject><subject>Assaying</subject><subject>Binding</subject><subject>Biological Assay</subject><subject>Biopolymers</subject><subject>Databases, Chemical</subject><subject>Fibrosis</subject><subject>High-Throughput Screening Assays - methods</subject><subject>HTS</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Matrix Metalloproteinase Inhibitors - analysis</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacology</subject><subject>meprin</subject><subject>Metalloendopeptidases - antagonists & inhibitors</subject><subject>Metalloendopeptidases - chemistry</subject><subject>NF449</subject><subject>Pilot Projects</subject><subject>Pilots</subject><subject>PPNDS</subject><subject>Reproducibility of Results</subject><subject>Screening</subject><subject>Substrate Specificity - drug effects</subject><subject>suramin</subject><subject>Time Factors</subject><subject>Zinc</subject><subject>zinc metalloproteinase</subject><issn>0006-3525</issn><issn>1097-0282</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1OVDEYhhsjkRFdeAOmS1kc6H87Sx0QSAhq1JiwaXrOfGdO9fzR9qhzWXIhXBOFYdgZXTVpn_fpl-9F6BUlB5QQdlj68YAxyfQTNKNkrgvCDHuKZoQQVXDJ5C56HuN3QoTglDxDu0wSYTSlM5SO4Ce0w9hBn_BQ48avGpyaMEyrZpwSjlUA6H2_wi5Gt47Y9Us8-nbYPuF6CNj3jS99GkK8c3SQXJudYUjgIsR8MQbf45s_9-mb6xdop3ZthJcP5x76-v74y-K0OP9wcrZ4e15UQgldUOGkUaySNM8N1FSmVspw7aA0WqrazI0pjSJ0yRSjNVUVBVI6V3KlKSvnfA-92XjzKFcTxGQ7HytoW9fDMEVLM6cYZ5r_G5X5a6Ho_L9QkZfOtc7o_gatwhBjgNrmRXQurC0l9q46m6uz99Vl9vWDdio7WD6S264ycLgBfvkW1n832XdnH7fKYpPwMcHvx4QLP6zSXEv77eLEXn5a8KPLz8Je8Fu4aLL6</recordid><startdate>201409</startdate><enddate>201409</enddate><creator>Madoux, Franck</creator><creator>Tredup, Claudia</creator><creator>Spicer, Timothy P.</creator><creator>Scampavia, Louis</creator><creator>Chase, Peter S.</creator><creator>Hodder, Peter S.</creator><creator>Fields, Gregg B.</creator><creator>Becker-Pauly, Christoph</creator><creator>Minond, Dmitriy</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7U5</scope><scope>8BQ</scope><scope>JG9</scope><scope>L7M</scope></search><sort><creationdate>201409</creationdate><title>Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β</title><author>Madoux, Franck ; Tredup, Claudia ; Spicer, Timothy P. ; Scampavia, Louis ; Chase, Peter S. ; Hodder, Peter S. ; Fields, Gregg B. ; Becker-Pauly, Christoph ; Minond, Dmitriy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4647-14a5862c51443e18c8f66837aeb8756f8988b8601d2621f16c1e0baab36712b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>actinonin</topic><topic>Assaying</topic><topic>Binding</topic><topic>Biological Assay</topic><topic>Biopolymers</topic><topic>Databases, Chemical</topic><topic>Fibrosis</topic><topic>High-Throughput Screening Assays - methods</topic><topic>HTS</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Matrix Metalloproteinase Inhibitors - analysis</topic><topic>Matrix Metalloproteinase Inhibitors - pharmacology</topic><topic>meprin</topic><topic>Metalloendopeptidases - antagonists & inhibitors</topic><topic>Metalloendopeptidases - chemistry</topic><topic>NF449</topic><topic>Pilot Projects</topic><topic>Pilots</topic><topic>PPNDS</topic><topic>Reproducibility of Results</topic><topic>Screening</topic><topic>Substrate Specificity - drug effects</topic><topic>suramin</topic><topic>Time Factors</topic><topic>Zinc</topic><topic>zinc metalloproteinase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Madoux, Franck</creatorcontrib><creatorcontrib>Tredup, Claudia</creatorcontrib><creatorcontrib>Spicer, Timothy P.</creatorcontrib><creatorcontrib>Scampavia, Louis</creatorcontrib><creatorcontrib>Chase, Peter S.</creatorcontrib><creatorcontrib>Hodder, Peter S.</creatorcontrib><creatorcontrib>Fields, Gregg B.</creatorcontrib><creatorcontrib>Becker-Pauly, Christoph</creatorcontrib><creatorcontrib>Minond, Dmitriy</creatorcontrib><collection>Istex</collection><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><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>METADEX</collection><collection>Materials Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><jtitle>Biopolymers</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Madoux, Franck</au><au>Tredup, Claudia</au><au>Spicer, Timothy P.</au><au>Scampavia, Louis</au><au>Chase, Peter S.</au><au>Hodder, Peter S.</au><au>Fields, Gregg B.</au><au>Becker-Pauly, Christoph</au><au>Minond, Dmitriy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β</atitle><jtitle>Biopolymers</jtitle><addtitle>Biopolymers</addtitle><date>2014-09</date><risdate>2014</risdate><volume>102</volume><issue>5</issue><spage>396</spage><epage>406</epage><pages>396-406</pages><issn>0006-3525</issn><eissn>1097-0282</eissn><abstract>ABSTRACT
Zinc metalloproteinases meprin α and meprin β are implicated in a variety of diseases, such as fibrosis, inflammation and neurodegeneration, however, there are no selective small molecule inhibitors that would allow to study their role in these processes. To address this lack of molecular tools, we have developed high throughput screening assays to enable discovery of inhibitors of both meprin α and meprin β and screened a collection of well characterized pharmaceutical agents (library of pharmaceutically active compounds, n = 1,280 compounds). Two compounds (PPNDS, NF449) confirmed their activity and selectivity for meprin β. Kinetic studies revealed competitive (PPNDS) and mixed competitive/noncompetitive (NF449) inhibition mechanisms suggesting that binding occurs in meprin β active site. Both PPNDS and NF449 exhibited low nanomolar IC50 and Ki values making them the most potent and selective inhibitors of meprin β reported to the date. These results demonstrate the ability of meprin α and β assays to identify selective compounds and discard artifacts of primary screening. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 396–406, 2014.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>25048711</pmid><doi>10.1002/bip.22527</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | actinonin Assaying Binding Biological Assay Biopolymers Databases, Chemical Fibrosis High-Throughput Screening Assays - methods HTS Humans Inhibitors Matrix Metalloproteinase Inhibitors - analysis Matrix Metalloproteinase Inhibitors - pharmacology meprin Metalloendopeptidases - antagonists & inhibitors Metalloendopeptidases - chemistry NF449 Pilot Projects Pilots PPNDS Reproducibility of Results Screening Substrate Specificity - drug effects suramin Time Factors Zinc zinc metalloproteinase |
| title | Development of high throughput screening assays and pilot screen for inhibitors of metalloproteases meprin α and β |
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