Yeast Based Small Molecule Screen for Inhibitors of SARS-CoV
Identifieur interne : 001374 ( Pmc/Curation ); précédent : 001373; suivant : 001375Yeast Based Small Molecule Screen for Inhibitors of SARS-CoV
Auteurs : Matthew Frieman [États-Unis] ; Dipanwita Basu [États-Unis] ; Krystal Matthews [États-Unis] ; Justin Taylor [États-Unis] ; Grant Jones [États-Unis] ; Raymond Pickles [États-Unis] ; Ralph Baric [États-Unis] ; Daniel A. Engel [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
Severe acute respiratory coronavirus (SARS-CoV) emerged in 2002, resulting in roughly 8000 cases worldwide and 10% mortality. The animal reservoirs for SARS-CoV precursors still exist and the likelihood of future outbreaks in the human population is high. The SARS-CoV papain-like protease (PLP) is an attractive target for pharmaceutical development because it is essential for virus replication and is conserved among human coronaviruses. A yeast-based assay was established for PLP activity that relies on the ability of PLP to induce a pronounced slow-growth phenotype when expressed in
Url:
DOI: 10.1371/journal.pone.0028479
PubMed: 22164298
PubMed Central: 3229576
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PMC:3229576Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>Severe acute respiratory coronavirus (SARS-CoV) emerged in 2002, resulting in roughly 8000 cases worldwide and 10% mortality. The animal reservoirs for SARS-CoV precursors still exist and the likelihood of future outbreaks in the human population is high. The SARS-CoV papain-like protease (PLP) is an attractive target for pharmaceutical development because it is essential for virus replication and is conserved among human coronaviruses. A yeast-based assay was established for PLP activity that relies on the ability of PLP to induce a pronounced slow-growth phenotype when expressed in <italic>S. cerevisiae</italic>
. Induction of the slow-growth phenotype was shown to take place over a 60-hour time course, providing the basis for conducting a screen for small molecules that restore growth by inhibiting the function of PLP. Five chemical suppressors of the slow-growth phenotype were identified from the 2000 member NIH Diversity Set library. One of these, NSC158362, potently inhibited SARS-CoV replication in cell culture without toxic effects on cells, and it specifically inhibited SARS-CoV replication but not influenza virus replication. The effect of NSC158362 on PLP protease, deubiquitinase and anti-interferon activities was investigated but the compound did not alter these activities. Another suppressor, NSC158011, demonstrated the ability to inhibit PLP protease activity in a cell-based assay. The identification of these inhibitors demonstrated a strong functional connection between the PLP-based yeast assay, the inhibitory compounds, and SARS-CoV biology. Furthermore the data with NSC158362 suggest a novel mechanism for inhibition of SARS-CoV replication that may involve an unknown activity of PLP, or alternatively a direct effect on a cellular target that modifies or bypasses PLP function in yeast and mammalian cells.</p>
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<journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id>
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<publisher><publisher-name>Public Library of Science</publisher-name>
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<article-id pub-id-type="doi">10.1371/journal.pone.0028479</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology</subject>
<subj-group><subject>Biochemistry</subject>
<subj-group><subject>Drug Discovery</subject>
</subj-group>
</subj-group>
<subj-group><subject>Biotechnology</subject>
<subj-group><subject>Drug Discovery</subject>
</subj-group>
</subj-group>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Mycology</subject>
<subj-group><subject>Yeast</subject>
</subj-group>
</subj-group>
<subj-group><subject>Emerging Infectious Diseases</subject>
<subject>Virology</subject>
</subj-group>
</subj-group>
<subj-group><subject>Model Organisms</subject>
<subj-group><subject>Yeast and Fungal Models</subject>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject>
<subj-group><subject>Drugs and Devices</subject>
<subj-group><subject>Drug Research and Development</subject>
<subj-group><subject>Drug Discovery</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Yeast Based Small Molecule Screen for Inhibitors of SARS-CoV</article-title>
<alt-title alt-title-type="running-head">SARS-CoV Inhibitor Screen</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Frieman</surname>
<given-names>Matthew</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Basu</surname>
<given-names>Dipanwita</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Matthews</surname>
<given-names>Krystal</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Taylor</surname>
<given-names>Justin</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jones</surname>
<given-names>Grant</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pickles</surname>
<given-names>Raymond</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Baric</surname>
<given-names>Ralph</given-names>
</name>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Engel</surname>
<given-names>Daniel A.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia, United States of America</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Microbiology and Immunology, Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>School of Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Thiel</surname>
<given-names>Volker</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">Kantonal Hospital St. Gallen, Switzerland</aff>
<author-notes><corresp id="cor1">* E-mail: <email>dae2s@virginia.edu</email>
</corresp>
<fn fn-type="con"><p>Conceived and designed the experiments: DE RB MF. Performed the experiments: MF DB KM JT GJ. Analyzed the data: MF DE. Contributed reagents/materials/analysis tools: MF RB DE. Wrote the paper: MF RB DE.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><year>2011</year>
</pub-date>
<pub-date pub-type="epub"><day>2</day>
<month>12</month>
<year>2011</year>
</pub-date>
<volume>6</volume>
<issue>12</issue>
<elocation-id>e28479</elocation-id>
<history><date date-type="received"><day>1</day>
<month>7</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>9</day>
<month>11</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>Frieman et al.</copyright-statement>
<copyright-year>2011</copyright-year>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>Severe acute respiratory coronavirus (SARS-CoV) emerged in 2002, resulting in roughly 8000 cases worldwide and 10% mortality. The animal reservoirs for SARS-CoV precursors still exist and the likelihood of future outbreaks in the human population is high. The SARS-CoV papain-like protease (PLP) is an attractive target for pharmaceutical development because it is essential for virus replication and is conserved among human coronaviruses. A yeast-based assay was established for PLP activity that relies on the ability of PLP to induce a pronounced slow-growth phenotype when expressed in <italic>S. cerevisiae</italic>
. Induction of the slow-growth phenotype was shown to take place over a 60-hour time course, providing the basis for conducting a screen for small molecules that restore growth by inhibiting the function of PLP. Five chemical suppressors of the slow-growth phenotype were identified from the 2000 member NIH Diversity Set library. One of these, NSC158362, potently inhibited SARS-CoV replication in cell culture without toxic effects on cells, and it specifically inhibited SARS-CoV replication but not influenza virus replication. The effect of NSC158362 on PLP protease, deubiquitinase and anti-interferon activities was investigated but the compound did not alter these activities. Another suppressor, NSC158011, demonstrated the ability to inhibit PLP protease activity in a cell-based assay. The identification of these inhibitors demonstrated a strong functional connection between the PLP-based yeast assay, the inhibitory compounds, and SARS-CoV biology. Furthermore the data with NSC158362 suggest a novel mechanism for inhibition of SARS-CoV replication that may involve an unknown activity of PLP, or alternatively a direct effect on a cellular target that modifies or bypasses PLP function in yeast and mammalian cells.</p>
</abstract>
<counts><page-count count="9"></page-count>
</counts>
</article-meta>
</front>
</pmc>
</record>
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