Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease
Identifieur interne : 000C24 ( Pmc/Corpus ); précédent : 000C23; suivant : 000C25Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease
Auteurs : Arun K. Ghosh ; Jun Takayama ; Yoann Aubin ; Kiira Ratia ; Rima Chaudhuri ; Yahira Baez ; Katrina Sleeman ; Melissa Coughlin ; Daniel B. Nichols ; Debbie C. Mulhearn ; Bellur S. Prabhakar ; Susan C. Baker ; Michael E. Johnson ; Andrew D. MesecarSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2009.
Abstract
We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies, and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Based upon the X-ray crystal structure of one of the potent inhibitors
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DOI: 10.1021/jm900611t
PubMed: 19645480
PubMed Central: 3148848
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease</title><author><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name><affiliation><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff></affiliation></author><author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name><affiliation><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff></affiliation></author><author><name sortKey="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</name><affiliation><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff></affiliation></author><author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name><affiliation><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff></affiliation></author><author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B." last="Nichols">Daniel B. Nichols</name><affiliation><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Prabhakar, Bellur S" sort="Prabhakar, Bellur S" uniqKey="Prabhakar B" first="Bellur S." last="Prabhakar">Bellur S. Prabhakar</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff></affiliation></author><author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C." last="Baker">Susan C. Baker</name><affiliation><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19645480</idno><idno type="pmc">3148848</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148848</idno><idno type="RBID">PMC:3148848</idno><idno type="doi">10.1021/jm900611t</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">000C24</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C24</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease</title><author><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name><affiliation><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff></affiliation></author><author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name><affiliation><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff></affiliation></author><author><name sortKey="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</name><affiliation><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff></affiliation></author><author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name><affiliation><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff></affiliation></author><author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B." last="Nichols">Daniel B. Nichols</name><affiliation><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Prabhakar, Bellur S" sort="Prabhakar, Bellur S" uniqKey="Prabhakar B" first="Bellur S." last="Prabhakar">Bellur S. Prabhakar</name><affiliation><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff></affiliation></author><author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C." last="Baker">Susan C. Baker</name><affiliation><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff></affiliation></author><author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author><author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name><affiliation><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies, and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Based upon the X-ray crystal structure of one of the potent inhibitors <bold>24</bold>-bound to SARS-CoV PLpro, a drug-design template was created. Our structure-based modification led to the design of a more potent inhibitor, <bold>2</bold> (enzyme IC<sub>50</sub> = 0.46 μM; antiviral EC<sub>50</sub> = 12.5 μM). Interestingly, its methylamine derivative <bold>49</bold> displayed good enzyme inhibitory potency (IC<sub>50</sub> = 1.3 μM) and most potent SARS antiviral activity (EC<sub>50</sub> = 2.5 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.</p></div></front></TEI><pmc article-type="research-article" xml:lang="en"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9716531</journal-id><journal-id journal-id-type="pubmed-jr-id">4938</journal-id><journal-id journal-id-type="nlm-ta">J Med Chem</journal-id><journal-title-group><journal-title>Journal of medicinal chemistry</journal-title></journal-title-group><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn></journal-meta><article-meta><article-id pub-id-type="pmid">19645480</article-id><article-id pub-id-type="pmc">3148848</article-id><article-id pub-id-type="doi">10.1021/jm900611t</article-id><article-id pub-id-type="manuscript">NIHMS310703</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ghosh</surname><given-names>Arun K.</given-names></name><xref rid="A1" ref-type="aff">†</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Takayama</surname><given-names>Jun</given-names></name><xref rid="A1" ref-type="aff">†</xref></contrib><contrib contrib-type="author"><name><surname>Aubin</surname><given-names>Yoann</given-names></name><xref rid="A1" ref-type="aff">†</xref></contrib><contrib contrib-type="author"><name><surname>Ratia</surname><given-names>Kiira</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib><contrib contrib-type="author"><name><surname>Chaudhuri</surname><given-names>Rima</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib><contrib contrib-type="author"><name><surname>Baez</surname><given-names>Yahira</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib><contrib contrib-type="author"><name><surname>Sleeman</surname><given-names>Katrina</given-names></name><xref rid="A3" ref-type="aff">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Coughlin</surname><given-names>Melissa</given-names></name><xref rid="A4" ref-type="aff">⊥⊥</xref></contrib><contrib contrib-type="author"><name><surname>Nichols</surname><given-names>Daniel B.</given-names></name><xref rid="A3" ref-type="aff">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Mulhearn</surname><given-names>Debbie C.</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib><contrib contrib-type="author"><name><surname>Prabhakar</surname><given-names>Bellur S.</given-names></name><xref rid="A4" ref-type="aff">⊥⊥</xref></contrib><contrib contrib-type="author"><name><surname>Baker</surname><given-names>Susan C.</given-names></name><xref rid="A3" ref-type="aff">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Johnson</surname><given-names>Michael E.</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib><contrib contrib-type="author"><name><surname>Mesecar</surname><given-names>Andrew D.</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib></contrib-group><aff id="A1"><label>†</label>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</aff><aff id="A2"><label>≠</label>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</aff><aff id="A3"><label>⊥</label>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</aff><aff id="A4"><label>⊥⊥</label>Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</aff><author-notes><corresp id="FN1"><label>*</label>The corresponding author: Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, Phone: (765)-494-5323; Fax: (765)-496-1612, <email>akghosh@purdue.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>19</day><month>7</month><year>2011</year></pub-date><pub-date pub-type="ppub"><day>27</day><month>8</month><year>2009</year></pub-date><pub-date pub-type="pmc-release"><day>2</day><month>8</month><year>2011</year></pub-date><volume>52</volume><issue>16</issue><fpage>5228</fpage><lpage>5240</lpage><abstract><p id="P1">We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies, and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Based upon the X-ray crystal structure of one of the potent inhibitors <bold>24</bold>-bound to SARS-CoV PLpro, a drug-design template was created. Our structure-based modification led to the design of a more potent inhibitor, <bold>2</bold> (enzyme IC<sub>50</sub> = 0.46 μM; antiviral EC<sub>50</sub> = 12.5 μM). Interestingly, its methylamine derivative <bold>49</bold> displayed good enzyme inhibitory potency (IC<sub>50</sub> = 1.3 μM) and most potent SARS antiviral activity (EC<sub>50</sub> = 2.5 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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