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 : 002F06 ( Main/Curation ); précédent : 002F05; suivant : 002F07Structure-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 [États-Unis] ; Jun Takayama [États-Unis] ; Yoann Aubin [États-Unis] ; Kiira Ratia [États-Unis] ; Rima Chaudhuri [États-Unis] ; Yahira Baez [États-Unis] ; Katrina Sleeman [États-Unis] ; Melissa Coughlin [États-Unis] ; Daniel B. Nichols [États-Unis] ; Debbie C. Mulhearn [États-Unis] ; Bellur S. Prabhakar [États-Unis] ; Susan C. Bakery [États-Unis] ; Michael E. Johnson [États-Unis] ; Andrew D. Mesecar [États-Unis]Source :
- Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2009.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Benzamides (), Benzamides (pharmacologie), Benzamides (synthèse chimique), Cellules Vero, Conception de médicament, Cristallographie aux rayons X, Cysteine endopeptidases, Inhibiteurs de protéases (), Inhibiteurs de protéases (pharmacologie), Inhibiteurs de protéases (synthèse chimique), Modèles moléculaires, Naphtalènes (), Naphtalènes (pharmacologie), Naphtalènes (synthèse chimique), Protéines virales (antagonistes et inhibiteurs), Relation quantitative structure-activité, Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- pharmacologie : Antiviraux, Benzamides, Inhibiteurs de protéases, Naphtalènes.
- synthèse chimique : Antiviraux, Benzamides, Inhibiteurs de protéases, Naphtalènes.
- Pascal (Inist)
- Animaux, Antiviraux, Benzamides, Cellules Vero, Conception de médicament, Cristallographie aux rayons X, Cysteine endopeptidases, Inhibiteurs de protéases, Modèles moléculaires, Naphtalènes, Relation quantitative structure-activité, Relation structure activité, Synthèse chimique, Antiviral, Cysteine endopeptidases, Virus du SRAS, Virus syndrome respiratoire aigu sévère, Composé non peptide, Inhibiteur enzyme, Dérivé du benzène, Dérivé du naphtalène, Amine secondaire, Carboxamide, In vitro, Modèle moléculaire, Complexe enzyme inhibiteur, Modélisation, Benzamide(2-méthyl-5-méthylamino-N-[1-(1-naphtyl)éthyl]).
English descriptors
- KwdEn :
- Animals, Antiviral, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Benzamides (chemical synthesis), Benzamides (chemistry), Benzamides (pharmacology), Benzene derivatives, Carboxamide, Chemical synthesis, Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases, Cysteine endopeptidases, Drug Design, Enzyme inhibitor, In vitro, Inhibitor enzyme complex, Modeling, Models, Molecular, Molecular model, Naphthalene derivatives, Naphthalenes (chemical synthesis), Naphthalenes (chemistry), Naphthalenes (pharmacology), Non peptide compound, Protease Inhibitors (chemical synthesis), Protease Inhibitors (chemistry), Protease Inhibitors (pharmacology), Quantitative Structure-Activity Relationship, SARS Virus (drug effects), SARS Virus (enzymology), Secondary amine, Severe acute respiratory syndrome virus, Structure activity relation, Vero Cells, Viral Proteins (antagonists & inhibitors).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Antiviral Agents, Benzamides, Naphthalenes, Protease Inhibitors.
- chemical , chemistry : Antiviral Agents, Benzamides, Naphthalenes, Protease Inhibitors.
- chemical , pharmacology : Antiviral Agents, Benzamides, Naphthalenes, Protease Inhibitors.
- drug effects : SARS Virus.
- enzymology : SARS Virus.
- Animals, Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases, Drug Design, Models, Molecular, Quantitative Structure-Activity Relationship, Vero Cells.
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. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC50 = 0.46 μM; antiviral EC50 = 6 μM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC50 = 1.3 uM) and the most potent SARS antiviral activity (EC50 = 5.2 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
Url:
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Pascal:09-0461730Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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>
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<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology and Immunology, University of lllinois</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
</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="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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 wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology and Immunology, University of lllinois</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bakery, Susan C" sort="Bakery, Susan C" uniqKey="Bakery S" first="Susan C." last="Bakery">Susan C. Bakery</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
<imprint><date when="2009">2009</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Antiviral</term>
<term>Antiviral Agents (chemical synthesis)</term>
<term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Benzamides (chemical synthesis)</term>
<term>Benzamides (chemistry)</term>
<term>Benzamides (pharmacology)</term>
<term>Benzene derivatives</term>
<term>Carboxamide</term>
<term>Chemical synthesis</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Cysteine Endopeptidases</term>
<term>Cysteine endopeptidases</term>
<term>Drug Design</term>
<term>Enzyme inhibitor</term>
<term>In vitro</term>
<term>Inhibitor enzyme complex</term>
<term>Modeling</term>
<term>Models, Molecular</term>
<term>Molecular model</term>
<term>Naphthalene derivatives</term>
<term>Naphthalenes (chemical synthesis)</term>
<term>Naphthalenes (chemistry)</term>
<term>Naphthalenes (pharmacology)</term>
<term>Non peptide compound</term>
<term>Protease Inhibitors (chemical synthesis)</term>
<term>Protease Inhibitors (chemistry)</term>
<term>Protease Inhibitors (pharmacology)</term>
<term>Quantitative Structure-Activity Relationship</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (enzymology)</term>
<term>Secondary amine</term>
<term>Severe acute respiratory syndrome virus</term>
<term>Structure activity relation</term>
<term>Vero Cells</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antiviraux ()</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Benzamides ()</term>
<term>Benzamides (pharmacologie)</term>
<term>Benzamides (synthèse chimique)</term>
<term>Cellules Vero</term>
<term>Conception de médicament</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases</term>
<term>Inhibiteurs de protéases ()</term>
<term>Inhibiteurs de protéases (pharmacologie)</term>
<term>Inhibiteurs de protéases (synthèse chimique)</term>
<term>Modèles moléculaires</term>
<term>Naphtalènes ()</term>
<term>Naphtalènes (pharmacologie)</term>
<term>Naphtalènes (synthèse chimique)</term>
<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Relation quantitative structure-activité</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (enzymologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term>
<term>Benzamides</term>
<term>Naphthalenes</term>
<term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Benzamides</term>
<term>Naphthalenes</term>
<term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Benzamides</term>
<term>Naphthalenes</term>
<term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Benzamides</term>
<term>Inhibiteurs de protéases</term>
<term>Naphtalènes</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term>
<term>Benzamides</term>
<term>Inhibiteurs de protéases</term>
<term>Naphtalènes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Cysteine Endopeptidases</term>
<term>Drug Design</term>
<term>Models, Molecular</term>
<term>Quantitative Structure-Activity Relationship</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term>
<term>Antiviraux</term>
<term>Benzamides</term>
<term>Cellules Vero</term>
<term>Conception de médicament</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases</term>
<term>Inhibiteurs de protéases</term>
<term>Modèles moléculaires</term>
<term>Naphtalènes</term>
<term>Relation quantitative structure-activité</term>
<term>Relation structure activité</term>
<term>Synthèse chimique</term>
<term>Antiviral</term>
<term>Cysteine endopeptidases</term>
<term>Virus du SRAS</term>
<term>Virus syndrome respiratoire aigu sévère</term>
<term>Composé non peptide</term>
<term>Inhibiteur enzyme</term>
<term>Dérivé du benzène</term>
<term>Dérivé du naphtalène</term>
<term>Amine secondaire</term>
<term>Carboxamide</term>
<term>In vitro</term>
<term>Modèle moléculaire</term>
<term>Complexe enzyme inhibiteur</term>
<term>Modélisation</term>
<term>Benzamide(2-méthyl-5-méthylamino-N-[1-(1-naphtyl)éthyl])</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">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. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC<sub>50</sub>
= 0.46 μM; antiviral EC<sub>50</sub>
= 6 μM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC<sub>50</sub>
= 1.3 uM) and the most potent SARS antiviral activity (EC<sub>50</sub>
= 5.2 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.</div>
</front>
</TEI>
<double idat="0022-2623:2009:Ghosh A:structure:based:design"><INIST><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">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 wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology and Immunology, University of lllinois</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
</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="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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 wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology and Immunology, University of lllinois</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bakery, Susan C" sort="Bakery, Susan C" uniqKey="Bakery S" first="Susan C." last="Bakery">Susan C. Bakery</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</name>
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<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name>
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<s3>USA</s3>
<sZ>4 aut.</sZ>
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<sZ>13 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">INIST</idno>
<idno type="inist">09-0461730</idno>
<date when="2009">2009</date>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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 wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
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</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
<affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive</s1>
<s2>West Lafayette, Indiana 47907</s2>
<s3>USA</s3>
<sZ>1 aut.</sZ>
<sZ>2 aut.</sZ>
<sZ>3 aut.</sZ>
<sZ>5 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>West Lafayette, Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</name>
<affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name>
<affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology and Immunology, University of lllinois</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
</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="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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 wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology and Immunology, University of lllinois</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>8 aut.</sZ>
<sZ>11 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Bakery, Susan C" sort="Bakery, Susan C" uniqKey="Bakery S" first="Susan C." last="Bakery">Susan C. Bakery</name>
<affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine</s1>
<s2>Maywood, Illinois 60153</s2>
<s3>USA</s3>
<sZ>7 aut.</sZ>
<sZ>9 aut.</sZ>
<sZ>12 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Maywood, Illinois 60153</wicri:noRegion>
<orgName type="university">Université de Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</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="4"><inist:fA14 i1="02"><s1>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 South Ashland Avenue</s1>
<s2>Chicago, Illinois 60607</s2>
<s3>USA</s3>
<sZ>4 aut.</sZ>
<sZ>6 aut.</sZ>
<sZ>10 aut.</sZ>
<sZ>13 aut.</sZ>
<sZ>14 aut.</sZ>
</inist:fA14>
<country>États-Unis</country>
<wicri:noRegion>Chicago, Illinois 60607</wicri:noRegion>
<orgName type="university">Université de l'Illinois à Chicago</orgName>
<placeName><settlement type="city">Chicago</settlement>
<region type="state">Illinois</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
<imprint><date when="2009">2009</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral</term>
<term>Benzene derivatives</term>
<term>Carboxamide</term>
<term>Chemical synthesis</term>
<term>Cysteine endopeptidases</term>
<term>Enzyme inhibitor</term>
<term>In vitro</term>
<term>Inhibitor enzyme complex</term>
<term>Modeling</term>
<term>Molecular model</term>
<term>Naphthalene derivatives</term>
<term>Non peptide compound</term>
<term>Secondary amine</term>
<term>Severe acute respiratory syndrome virus</term>
<term>Structure activity relation</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Relation structure activité</term>
<term>Synthèse chimique</term>
<term>Antiviral</term>
<term>Cysteine endopeptidases</term>
<term>Virus syndrome respiratoire aigu sévère</term>
<term>Composé non peptide</term>
<term>Inhibiteur enzyme</term>
<term>Dérivé du benzène</term>
<term>Dérivé du naphtalène</term>
<term>Amine secondaire</term>
<term>Carboxamide</term>
<term>In vitro</term>
<term>Modèle moléculaire</term>
<term>Complexe enzyme inhibiteur</term>
<term>Modélisation</term>
<term>Benzamide(2-méthyl-5-méthylamino-N-[1-(1-naphtyl)éthyl])</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">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. Upon the basis of the X-ray crystal structure of inhibitor 24-bound to SARS-CoV PLpro, a drug design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC<sub>50</sub>
= 0.46 μM; antiviral EC<sub>50</sub>
= 6 μM). Interestingly, its methylamine derivative, 49, displayed good enzyme inhibitory potency (IC<sub>50</sub>
= 1.3 uM) and the most potent SARS antiviral activity (EC<sub>50</sub>
= 5.2 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.</div>
</front>
</TEI>
</INIST>
<PMC><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 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="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</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>
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<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>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
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</affiliation>
</author>
<author><name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</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="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</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="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, University of Illinois, Chicago</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="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="Prabhakar, Bellur S" sort="Prabhakar, Bellur S" uniqKey="Prabhakar B" first="Bellur S." last="Prabhakar">Bellur S. Prabhakar</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, University of Illinois, Chicago</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>
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<placeName><region type="state">Illinois</region>
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<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 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>
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<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="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</name>
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<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>
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<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
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<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
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<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="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</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="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</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="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name>
<affiliation wicri:level="2"><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, University of Illinois, Chicago</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="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>
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</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 wicri:level="2"><nlm:aff id="A4">Department of Microbiology and Immunology, University of Illinois, Chicago, IL 60607</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, University of Illinois, Chicago</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>
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</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>
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</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name>
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<placeName><region type="state">Illinois</region>
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<series><title level="j">Journal of medicinal chemistry</title>
<idno type="ISSN">0022-2623</idno>
<idno type="eISSN">1520-4804</idno>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Antiviral Agents (chemical synthesis)</term>
<term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Benzamides (chemical synthesis)</term>
<term>Benzamides (chemistry)</term>
<term>Benzamides (pharmacology)</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Cysteine Endopeptidases</term>
<term>Drug Design</term>
<term>Models, Molecular</term>
<term>Naphthalenes (chemical synthesis)</term>
<term>Naphthalenes (chemistry)</term>
<term>Naphthalenes (pharmacology)</term>
<term>Protease Inhibitors (chemical synthesis)</term>
<term>Protease Inhibitors (chemistry)</term>
<term>Protease Inhibitors (pharmacology)</term>
<term>Quantitative Structure-Activity Relationship</term>
<term>SARS Virus (drug effects)</term>
<term>SARS Virus (enzymology)</term>
<term>Vero Cells</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antiviraux ()</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Benzamides ()</term>
<term>Benzamides (pharmacologie)</term>
<term>Benzamides (synthèse chimique)</term>
<term>Cellules Vero</term>
<term>Conception de médicament</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases</term>
<term>Inhibiteurs de protéases ()</term>
<term>Inhibiteurs de protéases (pharmacologie)</term>
<term>Inhibiteurs de protéases (synthèse chimique)</term>
<term>Modèles moléculaires</term>
<term>Naphtalènes ()</term>
<term>Naphtalènes (pharmacologie)</term>
<term>Naphtalènes (synthèse chimique)</term>
<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Relation quantitative structure-activité</term>
<term>Virus du SRAS ()</term>
<term>Virus du SRAS (enzymologie)</term>
</keywords>
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</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term>
<term>Benzamides</term>
<term>Naphthalenes</term>
<term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Benzamides</term>
<term>Naphthalenes</term>
<term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Benzamides</term>
<term>Naphthalenes</term>
<term>Protease Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Benzamides</term>
<term>Inhibiteurs de protéases</term>
<term>Naphtalènes</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term>
<term>Benzamides</term>
<term>Inhibiteurs de protéases</term>
<term>Naphtalènes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Cysteine Endopeptidases</term>
<term>Drug Design</term>
<term>Models, Molecular</term>
<term>Quantitative Structure-Activity Relationship</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Antiviraux</term>
<term>Benzamides</term>
<term>Cellules Vero</term>
<term>Conception de médicament</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases</term>
<term>Inhibiteurs de protéases</term>
<term>Modèles moléculaires</term>
<term>Naphtalènes</term>
<term>Relation quantitative structure-activité</term>
<term>Virus du SRAS</term>
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<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>
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