Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors
The synthesis and evaluation of a series of peptidomimetic boronic acid inhibitors of the HCV NS3/4A protease is described. Data on their biochemical and cellular activities, mutant protease activity, and genotype coverage is reported. A new series of NS3/4A protease boronic acid inhibitors is descr...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (19), p.5708-5711 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Boloor, Amogh Hanway, Denise Joshi, Maria Winn, David T. Mendez, Gabriel Walls, Marlena Wei, Ping Qian, Fuxin Zhang, Xiaoli Zhang, Yuliang Hepperle, Michael E. Li, Xinqiang Campbell, David A. Betancort, Juan M. |
| description | The synthesis and evaluation of a series of peptidomimetic boronic acid inhibitors of the HCV NS3/4A protease is described. Data on their biochemical and cellular activities, mutant protease activity, and genotype coverage is reported.
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound
28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC
50 of 25
nM in the replicon cell-based assay. |
| doi_str_mv | 10.1016/j.bmcl.2009.08.017 |
| format | Article |
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A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound
28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC
50 of 25
nM in the replicon cell-based assay.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.08.017</identifier><identifier>PMID: 19713109</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemical synthesis ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Boronic acids ; Boronic Acids - chemical synthesis ; Boronic Acids - chemistry ; Boronic Acids - pharmacology ; Carrier Proteins - antagonists & inhibitors ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Cell Line, Tumor ; Genotype ; HCV ; Hepacivirus - drug effects ; Hepacivirus - genetics ; Hepatitis C ; Hepatitis C - drug therapy ; Hepatitis C virus ; Humans ; Medical sciences ; Mutant Proteins - antagonists & inhibitors ; Mutant Proteins - metabolism ; NS3/4A ; Pharmacology. Drug treatments ; Protease Inhibitors - chemical synthesis ; Protease Inhibitors - chemistry ; Protease Inhibitors - pharmacology ; Viral Nonstructural Proteins - antagonists & inhibitors ; Viral Nonstructural Proteins - genetics ; Viral Nonstructural Proteins - metabolism ; Viral Proteins - antagonists & inhibitors ; Viral Proteins - genetics ; Viral Proteins - metabolism</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-10, Vol.19 (19), p.5708-5711</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c416t-7ec85f19b73550d891f3e050c36aeec4088a2607c5dc5883ef0a0b6f4430576a3</citedby><cites>FETCH-LOGICAL-c416t-7ec85f19b73550d891f3e050c36aeec4088a2607c5dc5883ef0a0b6f4430576a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2009.08.017$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3541,27915,27916,45986</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22002014$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19713109$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Boloor, Amogh</creatorcontrib><creatorcontrib>Hanway, Denise</creatorcontrib><creatorcontrib>Joshi, Maria</creatorcontrib><creatorcontrib>Winn, David T.</creatorcontrib><creatorcontrib>Mendez, Gabriel</creatorcontrib><creatorcontrib>Walls, Marlena</creatorcontrib><creatorcontrib>Wei, Ping</creatorcontrib><creatorcontrib>Qian, Fuxin</creatorcontrib><creatorcontrib>Zhang, Xiaoli</creatorcontrib><creatorcontrib>Zhang, Yuliang</creatorcontrib><creatorcontrib>Hepperle, Michael E.</creatorcontrib><creatorcontrib>Li, Xinqiang</creatorcontrib><creatorcontrib>Campbell, David A.</creatorcontrib><creatorcontrib>Betancort, Juan M.</creatorcontrib><title>Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The synthesis and evaluation of a series of peptidomimetic boronic acid inhibitors of the HCV NS3/4A protease is described. Data on their biochemical and cellular activities, mutant protease activity, and genotype coverage is reported.
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound
28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC
50 of 25
nM in the replicon cell-based assay.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemical synthesis</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Boronic acids</subject><subject>Boronic Acids - chemical synthesis</subject><subject>Boronic Acids - chemistry</subject><subject>Boronic Acids - pharmacology</subject><subject>Carrier Proteins - antagonists & inhibitors</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Genotype</subject><subject>HCV</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - genetics</subject><subject>Hepatitis C</subject><subject>Hepatitis C - drug therapy</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mutant Proteins - antagonists & inhibitors</subject><subject>Mutant Proteins - metabolism</subject><subject>NS3/4A</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Viral Nonstructural Proteins - antagonists & inhibitors</subject><subject>Viral Nonstructural Proteins - genetics</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Viral Proteins - antagonists & inhibitors</subject><subject>Viral Proteins - genetics</subject><subject>Viral Proteins - metabolism</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFq3DAQhkVpabZpX6CH4kvTk52RJVky5BKWtCmE5JCk9CZkeUy02NZG0gb27SOzS3vLQYwO3_zMfEPIVwoVBdqcb6pusmNVA7QVqAqofEdWlDe8ZBzEe7KCtoFStfzvCfkU4waAcuD8IzmhraSMQrsij_f7OT1hdLEwc59fci8umLEwdvmlfeGH4nr9p7i9Z-f8stjiNrneT27C5GzR-eDnXI11feHmJ9e55EP8TD4MZoz45VhPyePPq4f1dXlz9-v3-vKmtJw2qZRolRho20kmBPSqpQNDEGBZYxAtB6VM3YC0ordCKYYDGOiagXMGQjaGnZIfh9xt8M87jElPLlocRzOj30Ut2bKwkCyTZ2-SNQUleQ0ZrA-gDT7GgIPeBjeZsNcU9KJdb_SiXS_aNSidteemb8f0XTdh_7_l6DkD34-AidaMQzCzdfEfV-ewOl8ncxcHDrO1F4dBR-twtti7gDbp3ru35ngFu6KfUw</recordid><startdate>20091001</startdate><enddate>20091001</enddate><creator>Boloor, Amogh</creator><creator>Hanway, Denise</creator><creator>Joshi, Maria</creator><creator>Winn, David T.</creator><creator>Mendez, Gabriel</creator><creator>Walls, Marlena</creator><creator>Wei, Ping</creator><creator>Qian, Fuxin</creator><creator>Zhang, Xiaoli</creator><creator>Zhang, Yuliang</creator><creator>Hepperle, Michael E.</creator><creator>Li, Xinqiang</creator><creator>Campbell, David A.</creator><creator>Betancort, Juan M.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</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>7QO</scope><scope>7T7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20091001</creationdate><title>Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors</title><author>Boloor, Amogh ; Hanway, Denise ; Joshi, Maria ; Winn, David T. ; Mendez, Gabriel ; Walls, Marlena ; Wei, Ping ; Qian, Fuxin ; Zhang, Xiaoli ; Zhang, Yuliang ; Hepperle, Michael E. ; Li, Xinqiang ; Campbell, David A. ; Betancort, Juan M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-7ec85f19b73550d891f3e050c36aeec4088a2607c5dc5883ef0a0b6f4430576a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Antibiotics. 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Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Viral Nonstructural Proteins - antagonists & inhibitors</topic><topic>Viral Nonstructural Proteins - genetics</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>Viral Proteins - antagonists & inhibitors</topic><topic>Viral Proteins - genetics</topic><topic>Viral Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boloor, Amogh</creatorcontrib><creatorcontrib>Hanway, Denise</creatorcontrib><creatorcontrib>Joshi, Maria</creatorcontrib><creatorcontrib>Winn, David T.</creatorcontrib><creatorcontrib>Mendez, Gabriel</creatorcontrib><creatorcontrib>Walls, Marlena</creatorcontrib><creatorcontrib>Wei, Ping</creatorcontrib><creatorcontrib>Qian, Fuxin</creatorcontrib><creatorcontrib>Zhang, Xiaoli</creatorcontrib><creatorcontrib>Zhang, Yuliang</creatorcontrib><creatorcontrib>Hepperle, Michael E.</creatorcontrib><creatorcontrib>Li, Xinqiang</creatorcontrib><creatorcontrib>Campbell, David A.</creatorcontrib><creatorcontrib>Betancort, Juan M.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boloor, Amogh</au><au>Hanway, Denise</au><au>Joshi, Maria</au><au>Winn, David T.</au><au>Mendez, Gabriel</au><au>Walls, Marlena</au><au>Wei, Ping</au><au>Qian, Fuxin</au><au>Zhang, Xiaoli</au><au>Zhang, Yuliang</au><au>Hepperle, Michael E.</au><au>Li, Xinqiang</au><au>Campbell, David A.</au><au>Betancort, Juan M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>19</volume><issue>19</issue><spage>5708</spage><epage>5711</epage><pages>5708-5711</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The synthesis and evaluation of a series of peptidomimetic boronic acid inhibitors of the HCV NS3/4A protease is described. Data on their biochemical and cellular activities, mutant protease activity, and genotype coverage is reported.
A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound
28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC
50 of 25
nM in the replicon cell-based assay.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19713109</pmid><doi>10.1016/j.bmcl.2009.08.017</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2009-10, Vol.19 (19), p.5708-5711 |
| issn | 0960-894X 1464-3405 |
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| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Biological and medical sciences Boronic acids Boronic Acids - chemical synthesis Boronic Acids - chemistry Boronic Acids - pharmacology Carrier Proteins - antagonists & inhibitors Carrier Proteins - genetics Carrier Proteins - metabolism Cell Line, Tumor Genotype HCV Hepacivirus - drug effects Hepacivirus - genetics Hepatitis C Hepatitis C - drug therapy Hepatitis C virus Humans Medical sciences Mutant Proteins - antagonists & inhibitors Mutant Proteins - metabolism NS3/4A Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Viral Nonstructural Proteins - antagonists & inhibitors Viral Nonstructural Proteins - genetics Viral Nonstructural Proteins - metabolism Viral Proteins - antagonists & inhibitors Viral Proteins - genetics Viral Proteins - metabolism |
| title | Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors |
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