Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation
Identifieur interne : 000C17 ( Pmc/Curation ); précédent : 000C16; suivant : 000C18Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation
Auteurs : Arun K. Ghosh [États-Unis] ; Jun Takayama [États-Unis] ; Kalapala Venkateswara Rao [États-Unis] ; Kiira Ratia [États-Unis] ; Rima Chaudhuri [États-Unis] ; Debbie C. Mulhearn [États-Unis] ; Hyun Lee [États-Unis] ; Daniel B. Nichols [États-Unis] ; Surendranath Baliji [États-Unis] ; Susan C. Baker [États-Unis] ; Michael E. Johnson [États-Unis] ; Andrew D. Mesecar [États-Unis]Source :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2010.
Abstract
The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound
Url:
DOI: 10.1021/jm1004489
PubMed: 20527968
PubMed Central: 2918394
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Ghosh</name><affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name><affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Rao, Kalapala Venkateswara" sort="Rao, Kalapala Venkateswara" uniqKey="Rao K" first="Kalapala Venkateswara" last="Rao">Kalapala Venkateswara Rao</name><affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name><affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. 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Ghosh</name><affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name><affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Rao, Kalapala Venkateswara" sort="Rao, Kalapala Venkateswara" uniqKey="Rao K" first="Kalapala Venkateswara" last="Rao">Kalapala Venkateswara Rao</name><affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea></affiliation></author><author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name><affiliation wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea></affiliation></author><author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name><affiliation wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea></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 wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea></affiliation></author><author><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name><affiliation wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea></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 wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea></affiliation></author><author><name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name><affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea></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 wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea></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 wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea></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 wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea></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="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound <bold>3</bold> (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (<italic>S</italic>)-Me inhibitor <bold>15h</bold> (enzyme IC<sub>50</sub> = 0.56 μM; antiviral EC<sub>50</sub> = 9.1 μM) and the corresponding (<italic>R</italic>)-Me <bold>15g</bold> (IC<sub>50</sub> = 0.32 μM; antiviral EC<sub>50</sub> = 9.1 μM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of <bold>15g</bold>-bound SARS-CoV PLpro and a corresponding model of <bold>15h</bold> docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.</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>Journal of medicinal chemistry</journal-title><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn></journal-meta><article-meta><article-id pub-id-type="pmid">20527968</article-id><article-id pub-id-type="pmc">2918394</article-id><article-id pub-id-type="doi">10.1021/jm1004489</article-id><article-id pub-id-type="manuscript">NIHMS212885</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Ghosh</surname><given-names>Arun K.</given-names></name><xref rid="FN1" ref-type="author-notes">*</xref><xref rid="A1" ref-type="aff">†</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>Rao</surname><given-names>Kalapala Venkateswara</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>Mulhearn</surname><given-names>Debbie C.</given-names></name><xref rid="A2" ref-type="aff">≠</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Hyun</given-names></name><xref rid="A2" 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>Baliji</surname><given-names>Surendranath</given-names></name><xref rid="A3" 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><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>14</day><month>7</month><year>2010</year></pub-date><pub-date pub-type="ppub"><day>8</day><month>7</month><year>2010</year></pub-date><pub-date pub-type="pmc-release"><day>8</day><month>7</month><year>2011</year></pub-date><volume>53</volume><issue>13</issue><fpage>4968</fpage><lpage>4979</lpage><abstract><p id="P1">The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound <bold>3</bold> (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (<italic>S</italic>)-Me inhibitor <bold>15h</bold> (enzyme IC<sub>50</sub> = 0.56 μM; antiviral EC<sub>50</sub> = 9.1 μM) and the corresponding (<italic>R</italic>)-Me <bold>15g</bold> (IC<sub>50</sub> = 0.32 μM; antiviral EC<sub>50</sub> = 9.1 μM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of <bold>15g</bold>-bound SARS-CoV PLpro and a corresponding model of <bold>15h</bold> docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.</p></abstract><contract-num rid="AI1">P01 AI060915-050003
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