Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase
Our current study reports the first K M optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K M = 80 μM) was converted from a substr...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2011-04, Vol.54 (8), p.2933-2943 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 2943 |
|---|---|
| container_issue | 8 |
| container_start_page | 2933 |
| container_title | Journal of medicinal chemistry |
| container_volume | 54 |
| creator | Bahta, Medhanit Lountos, George T Dyas, Beverly Kim, Sung-Eun Ulrich, Robert G Waugh, David S Burke, Terrence R |
| description | Our current study reports the first K M optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K M = 80 μM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC50 = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH. |
| doi_str_mv | 10.1021/jm200022g |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3085962</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>863426859</sourcerecordid><originalsourceid>FETCH-LOGICAL-a497t-91b3b72eca88301bf576e4d8f8dea79cf2650ecd9f4673dcfe793d5c3a5807883</originalsourceid><addsrcrecordid>eNptkstuEzEUhi0EoiGw4AWQhYSgiwFf5rpBKuWSShHpgi66shzPccbRjD21nYrwTDwkDhMikFhZ8vnOf_5zQeg5JW8pYfTddmCEEMY2D9CMFoxkeU3yh2h2-MtYyfgZehLCNjGcMv4YnTGa55w2xQz9vImmNz9kNM5ip_FXE70bO7D7fuxcGDsZIWBpW7z6bgbIPsgALV6azZShncexA_wR7qF34wA2_laR1g2ulx5faG2siXt8ZTuzNtH5cAAOObfgQ4pJPEKIJuDVLoLH195FMBYv8JtbNy7O8fXRRir8FD3Ssg_w7PjO0c3nT98uF9ly9eXq8mKZybypYtbQNV9XDJSsa07oWhdVCXlb67oFWTVKs7IgoNpG52XFW6WhanhbKC6LmlQpZ47eT7rjbj1Aq1JXXvZi9GaQfi-cNOLfiDWd2Lh7wUldNGnec_RyEnCpMxGUiaA65awFFQUlOanrKkGvj1W8u9ulGYjBBAV9Ly24XRB1yXNWJsFEnk-k8i4ED_pkhRJxuABxuoDEvvjb-4n8s_IEvJoAqYLYup23aZT_EfoFA-K8Gw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>863426859</pqid></control><display><type>article</type><title>Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase</title><source>MEDLINE</source><source>ACS Publications</source><creator>Bahta, Medhanit ; Lountos, George T ; Dyas, Beverly ; Kim, Sung-Eun ; Ulrich, Robert G ; Waugh, David S ; Burke, Terrence R</creator><creatorcontrib>Bahta, Medhanit ; Lountos, George T ; Dyas, Beverly ; Kim, Sung-Eun ; Ulrich, Robert G ; Waugh, David S ; Burke, Terrence R ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Our current study reports the first K M optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K M = 80 μM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC50 = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm200022g</identifier><identifier>PMID: 21443195</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>60 APPLIED LIFE SCIENCES ; AFFINITY ; Animals ; Bacteria - drug effects ; Bacteria - growth & development ; Bacterial Outer Membrane Proteins - antagonists & inhibitors ; BASIC BIOLOGICAL SCIENCES ; Cell Line ; Crystallography, X-Ray ; DESIGN ; Drug Design ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - toxicity ; INHIBITION ; Inhibitory Concentration 50 ; Mice ; Models, Molecular ; OPTIMIZATION ; OXIMES ; Oximes - chemistry ; PHOSPHATASES ; PHOSPHATES ; Phosphates - chemistry ; Protein Tyrosine Phosphatases - antagonists & inhibitors ; PROTEINS ; Spectrometry, Mass, Electrospray Ionization ; SUBSTRATES ; WATER ; Yersinia pestis - enzymology</subject><ispartof>Journal of medicinal chemistry, 2011-04, Vol.54 (8), p.2933-2943</ispartof><rights>Copyright © 2011 U.S. Government</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a497t-91b3b72eca88301bf576e4d8f8dea79cf2650ecd9f4673dcfe793d5c3a5807883</citedby><cites>FETCH-LOGICAL-a497t-91b3b72eca88301bf576e4d8f8dea79cf2650ecd9f4673dcfe793d5c3a5807883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm200022g$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm200022g$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21443195$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1040887$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Bahta, Medhanit</creatorcontrib><creatorcontrib>Lountos, George T</creatorcontrib><creatorcontrib>Dyas, Beverly</creatorcontrib><creatorcontrib>Kim, Sung-Eun</creatorcontrib><creatorcontrib>Ulrich, Robert G</creatorcontrib><creatorcontrib>Waugh, David S</creatorcontrib><creatorcontrib>Burke, Terrence R</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Our current study reports the first K M optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K M = 80 μM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC50 = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>AFFINITY</subject><subject>Animals</subject><subject>Bacteria - drug effects</subject><subject>Bacteria - growth & development</subject><subject>Bacterial Outer Membrane Proteins - antagonists & inhibitors</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Cell Line</subject><subject>Crystallography, X-Ray</subject><subject>DESIGN</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - toxicity</subject><subject>INHIBITION</subject><subject>Inhibitory Concentration 50</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>OPTIMIZATION</subject><subject>OXIMES</subject><subject>Oximes - chemistry</subject><subject>PHOSPHATASES</subject><subject>PHOSPHATES</subject><subject>Phosphates - chemistry</subject><subject>Protein Tyrosine Phosphatases - antagonists & inhibitors</subject><subject>PROTEINS</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>SUBSTRATES</subject><subject>WATER</subject><subject>Yersinia pestis - enzymology</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkstuEzEUhi0EoiGw4AWQhYSgiwFf5rpBKuWSShHpgi66shzPccbRjD21nYrwTDwkDhMikFhZ8vnOf_5zQeg5JW8pYfTddmCEEMY2D9CMFoxkeU3yh2h2-MtYyfgZehLCNjGcMv4YnTGa55w2xQz9vImmNz9kNM5ip_FXE70bO7D7fuxcGDsZIWBpW7z6bgbIPsgALV6azZShncexA_wR7qF34wA2_laR1g2ulx5faG2siXt8ZTuzNtH5cAAOObfgQ4pJPEKIJuDVLoLH195FMBYv8JtbNy7O8fXRRir8FD3Ssg_w7PjO0c3nT98uF9ly9eXq8mKZybypYtbQNV9XDJSsa07oWhdVCXlb67oFWTVKs7IgoNpG52XFW6WhanhbKC6LmlQpZ47eT7rjbj1Aq1JXXvZi9GaQfi-cNOLfiDWd2Lh7wUldNGnec_RyEnCpMxGUiaA65awFFQUlOanrKkGvj1W8u9ulGYjBBAV9Ly24XRB1yXNWJsFEnk-k8i4ED_pkhRJxuABxuoDEvvjb-4n8s_IEvJoAqYLYup23aZT_EfoFA-K8Gw</recordid><startdate>20110428</startdate><enddate>20110428</enddate><creator>Bahta, Medhanit</creator><creator>Lountos, George T</creator><creator>Dyas, Beverly</creator><creator>Kim, Sung-Eun</creator><creator>Ulrich, Robert G</creator><creator>Waugh, David S</creator><creator>Burke, Terrence R</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><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20110428</creationdate><title>Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase</title><author>Bahta, Medhanit ; Lountos, George T ; Dyas, Beverly ; Kim, Sung-Eun ; Ulrich, Robert G ; Waugh, David S ; Burke, Terrence R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a497t-91b3b72eca88301bf576e4d8f8dea79cf2650ecd9f4673dcfe793d5c3a5807883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>AFFINITY</topic><topic>Animals</topic><topic>Bacteria - drug effects</topic><topic>Bacteria - growth & development</topic><topic>Bacterial Outer Membrane Proteins - antagonists & inhibitors</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Cell Line</topic><topic>Crystallography, X-Ray</topic><topic>DESIGN</topic><topic>Drug Design</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - toxicity</topic><topic>INHIBITION</topic><topic>Inhibitory Concentration 50</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>OPTIMIZATION</topic><topic>OXIMES</topic><topic>Oximes - chemistry</topic><topic>PHOSPHATASES</topic><topic>PHOSPHATES</topic><topic>Phosphates - chemistry</topic><topic>Protein Tyrosine Phosphatases - antagonists & inhibitors</topic><topic>PROTEINS</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>SUBSTRATES</topic><topic>WATER</topic><topic>Yersinia pestis - enzymology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bahta, Medhanit</creatorcontrib><creatorcontrib>Lountos, George T</creatorcontrib><creatorcontrib>Dyas, Beverly</creatorcontrib><creatorcontrib>Kim, Sung-Eun</creatorcontrib><creatorcontrib>Ulrich, Robert G</creatorcontrib><creatorcontrib>Waugh, David S</creatorcontrib><creatorcontrib>Burke, Terrence R</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</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><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bahta, Medhanit</au><au>Lountos, George T</au><au>Dyas, Beverly</au><au>Kim, Sung-Eun</au><au>Ulrich, Robert G</au><au>Waugh, David S</au><au>Burke, Terrence R</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-04-28</date><risdate>2011</risdate><volume>54</volume><issue>8</issue><spage>2933</spage><epage>2943</epage><pages>2933-2943</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Our current study reports the first K M optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K M = 80 μM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC50 = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21443195</pmid><doi>10.1021/jm200022g</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2011-04, Vol.54 (8), p.2933-2943 |
| issn | 0022-2623 1520-4804 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3085962 |
| source | MEDLINE; ACS Publications |
| subjects | 60 APPLIED LIFE SCIENCES AFFINITY Animals Bacteria - drug effects Bacteria - growth & development Bacterial Outer Membrane Proteins - antagonists & inhibitors BASIC BIOLOGICAL SCIENCES Cell Line Crystallography, X-Ray DESIGN Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Enzyme Inhibitors - toxicity INHIBITION Inhibitory Concentration 50 Mice Models, Molecular OPTIMIZATION OXIMES Oximes - chemistry PHOSPHATASES PHOSPHATES Phosphates - chemistry Protein Tyrosine Phosphatases - antagonists & inhibitors PROTEINS Spectrometry, Mass, Electrospray Ionization SUBSTRATES WATER Yersinia pestis - enzymology |
| title | Utilization of Nitrophenylphosphates and Oxime-Based Ligation for the Development of Nanomolar Affinity Inhibitors of the Yersinia pestis Outer Protein H (YopH) Phosphatase |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-08T02%3A52%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Utilization%20of%20Nitrophenylphosphates%20and%20Oxime-Based%20Ligation%20for%20the%20Development%20of%20Nanomolar%20Affinity%20Inhibitors%20of%20the%20Yersinia%20pestis%20Outer%20Protein%20H%20(YopH)%20Phosphatase&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Bahta,%20Medhanit&rft.aucorp=Argonne%20National%20Lab.%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2011-04-28&rft.volume=54&rft.issue=8&rft.spage=2933&rft.epage=2943&rft.pages=2933-2943&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm200022g&rft_dat=%3Cproquest_pubme%3E863426859%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=863426859&rft_id=info:pmid/21443195&rfr_iscdi=true |