High-Throughput Screening Identifies Inhibitors of the SARS Coronavirus Main Proteinase
The causative agent of severe acute respiratory syndrome (SARS) has been identified as a novel coronavirus, SARS-CoV. The main proteinase of SARS-CoV, 3CL pro, is an attractive target for therapeutics against SARS owing to its fundamental role in viral replication. We sought to identify novel inhibi...
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| Veröffentlicht in: | Chemistry & biology 2004-10, Vol.11 (10), p.1445-1453 |
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| creator | Blanchard, Jan E. Elowe, Nadine H. Huitema, Carly Fortin, Pascal D. Cechetto, Jonathan D. Eltis, Lindsay D. Brown, Eric D. |
| description | The causative agent of severe acute respiratory syndrome (SARS) has been identified as a novel coronavirus, SARS-CoV. The main proteinase of SARS-CoV, 3CL
pro, is an attractive target for therapeutics against SARS owing to its fundamental role in viral replication. We sought to identify novel inhibitors of 3CL
pro to advance the development of appropriate therapies in the treatment of SARS. 3CL
pro was cloned, expressed, and purified from the Tor2 isolate. A quenched fluorescence resonance energy transfer assay was developed for 3CL
pro to screen the proteinase against 50,000 drug-like small molecules on a fully automated system. The primary screen identified 572 hits; through a series of virtual and experimental filters, this number was reduced to five novel small molecules that show potent inhibitory activity (
IC
50
= 0.5–7 μM) toward SARS-CoV 3CL
pro. |
| doi_str_mv | 10.1016/j.chembiol.2004.08.011 |
| format | Article |
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pro, is an attractive target for therapeutics against SARS owing to its fundamental role in viral replication. We sought to identify novel inhibitors of 3CL
pro to advance the development of appropriate therapies in the treatment of SARS. 3CL
pro was cloned, expressed, and purified from the Tor2 isolate. A quenched fluorescence resonance energy transfer assay was developed for 3CL
pro to screen the proteinase against 50,000 drug-like small molecules on a fully automated system. The primary screen identified 572 hits; through a series of virtual and experimental filters, this number was reduced to five novel small molecules that show potent inhibitory activity (
IC
50
= 0.5–7 μM) toward SARS-CoV 3CL
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pro, is an attractive target for therapeutics against SARS owing to its fundamental role in viral replication. We sought to identify novel inhibitors of 3CL
pro to advance the development of appropriate therapies in the treatment of SARS. 3CL
pro was cloned, expressed, and purified from the Tor2 isolate. A quenched fluorescence resonance energy transfer assay was developed for 3CL
pro to screen the proteinase against 50,000 drug-like small molecules on a fully automated system. The primary screen identified 572 hits; through a series of virtual and experimental filters, this number was reduced to five novel small molecules that show potent inhibitory activity (
IC
50
= 0.5–7 μM) toward SARS-CoV 3CL
pro.</description><subject>Animals</subject><subject>Antiviral Agents - isolation & purification</subject><subject>Antiviral Agents - pharmacology</subject><subject>Cattle</subject><subject>Coronavirus 3C Proteases</subject><subject>Cysteine Endopeptidases</subject><subject>Endopeptidases - metabolism</subject><subject>Mass Spectrometry - methods</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - isolation & purification</subject><subject>Protease Inhibitors - pharmacology</subject><subject>SARS coronavirus</subject><subject>SARS Virus - drug effects</subject><subject>SARS Virus - enzymology</subject><subject>Viral Proteins - antagonists & inhibitors</subject><subject>Viral Proteins - metabolism</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1v1DAQtRCIlpa_UPnELcGOv5ILoloVulJRUbeIo-XYk41XWXuxk5X492TZ5aOn-jKW5s17b-YhdEVJSQmV7zel7WHb-jiUFSG8JHVJKH2BzmmtmoIyQl_Of6J4IURFz9CbnDeEEFo38jU6o4LXDVX0HH2_9eu-eOxTnNb9bhrxyiaA4MMaLx2E0XceMl6G3rd-jCnj2OGxB7y6fljhRUwxmL1PU8ZfjA_4a4oj-GAyXKJXnRkyvD3VC_Tt083j4ra4u_-8XFzfFVZIPhYCJFNN1Trmms64ylUEjDSzOcZrU3eKCaYqRoSTllnecKms7NT82pYQW7EL9OHIu5vaLTg7W05m0Lvktyb91NF4_bQTfK_Xca_VrCAaPhO8OxGk-GOCPOqtzxaGwQSIU9ZSNopzSp8FUsVFzeSBUR6BNsWcE3R_3VCiD-Hpjf4Tnj6Ep0mtyW-Fq_93-Td2SmsGfDwCYL7o3kPS2XoIFpxPYEfton9O4xcTvK-Y</recordid><startdate>20041001</startdate><enddate>20041001</enddate><creator>Blanchard, Jan E.</creator><creator>Elowe, Nadine H.</creator><creator>Huitema, Carly</creator><creator>Fortin, Pascal D.</creator><creator>Cechetto, Jonathan D.</creator><creator>Eltis, Lindsay D.</creator><creator>Brown, Eric D.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</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>7U9</scope><scope>H94</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20041001</creationdate><title>High-Throughput Screening Identifies Inhibitors of the SARS Coronavirus Main Proteinase</title><author>Blanchard, Jan E. ; 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The main proteinase of SARS-CoV, 3CL
pro, is an attractive target for therapeutics against SARS owing to its fundamental role in viral replication. We sought to identify novel inhibitors of 3CL
pro to advance the development of appropriate therapies in the treatment of SARS. 3CL
pro was cloned, expressed, and purified from the Tor2 isolate. A quenched fluorescence resonance energy transfer assay was developed for 3CL
pro to screen the proteinase against 50,000 drug-like small molecules on a fully automated system. The primary screen identified 572 hits; through a series of virtual and experimental filters, this number was reduced to five novel small molecules that show potent inhibitory activity (
IC
50
= 0.5–7 μM) toward SARS-CoV 3CL
pro.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>15489171</pmid><doi>10.1016/j.chembiol.2004.08.011</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Access via ScienceDirect (Elsevier); Free Full-Text Journals in Chemistry |
| subjects | Animals Antiviral Agents - isolation & purification Antiviral Agents - pharmacology Cattle Coronavirus 3C Proteases Cysteine Endopeptidases Endopeptidases - metabolism Mass Spectrometry - methods Protease Inhibitors - chemistry Protease Inhibitors - isolation & purification Protease Inhibitors - pharmacology SARS coronavirus SARS Virus - drug effects SARS Virus - enzymology Viral Proteins - antagonists & inhibitors Viral Proteins - metabolism |
| title | High-Throughput Screening Identifies Inhibitors of the SARS Coronavirus Main Proteinase |
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