Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation
Identifieur interne : 002151 ( Ncbi/Merge ); précédent : 002150; suivant : 002152Severe 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.
Descripteurs français
- KwdFr :
- Animaux, Antienzymes (), Antienzymes (métabolisme), Antienzymes (pharmacologie), Antienzymes (synthèse chimique), Antiviraux (), Antiviraux (métabolisme), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cellules Vero, Concentration inhibitrice 50, Cristallographie aux rayons X, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Modèles moléculaires, Pipéridines (), Pipéridines (métabolisme), Pipéridines (pharmacologie), Pipéridines (synthèse chimique), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Relation structure-activité, Réplication virale (), Spectrométrie de masse, Spectroscopie par résonance magnétique, Syndrome respiratoire aigu sévère (traitement médicamenteux), Syndrome respiratoire aigu sévère (virologie), Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Antienzymes, Antiviraux, Cysteine endopeptidases, Pipéridines, Protéines virales.
- pharmacologie : Antienzymes, Antiviraux, Pipéridines.
- synthèse chimique : Antienzymes, Antiviraux, Pipéridines.
- traitement médicamenteux : Syndrome respiratoire aigu sévère.
- virologie : Syndrome respiratoire aigu sévère.
- Animaux, Antienzymes, Antiviraux, Cellules Vero, Concentration inhibitrice 50, Cristallographie aux rayons X, Cysteine endopeptidases, Modèles moléculaires, Pipéridines, Protéines virales, Relation structure-activité, Réplication virale, Spectrométrie de masse, Spectroscopie par résonance magnétique.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemical synthesis), Antiviral Agents (chemistry), Antiviral Agents (metabolism), Antiviral Agents (pharmacology), Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Enzyme Inhibitors (chemical synthesis), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (metabolism), Enzyme Inhibitors (pharmacology), Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mass Spectrometry, Models, Molecular, Piperidines (chemical synthesis), Piperidines (chemistry), Piperidines (metabolism), Piperidines (pharmacology), SARS Virus (enzymology), Severe Acute Respiratory Syndrome (drug therapy), Severe Acute Respiratory Syndrome (virology), Structure-Activity Relationship, Vero Cells, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (metabolism), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemical synthesis : Antiviral Agents, Enzyme Inhibitors, Piperidines.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Enzyme Inhibitors, Piperidines, Viral Proteins.
- chemical , metabolism : Antiviral Agents, Cysteine Endopeptidases, Enzyme Inhibitors, Piperidines, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Enzyme Inhibitors, Piperidines.
- drug effects : Virus Replication.
- drug therapy : Severe Acute Respiratory Syndrome.
- enzymology : SARS Virus.
- virology : Severe Acute Respiratory Syndrome.
- Animals, Chlorocebus aethiops, Crystallography, X-Ray, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mass Spectrometry, Models, Molecular, Structure-Activity Relationship, Vero Cells.
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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PMC:2918394Le document en format XML
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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 (metabolism)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Cysteine Endopeptidases (chemistry)</term>
<term>Cysteine Endopeptidases (metabolism)</term>
<term>Enzyme Inhibitors (chemical synthesis)</term>
<term>Enzyme Inhibitors (chemistry)</term>
<term>Enzyme Inhibitors (metabolism)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Inhibitory Concentration 50</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mass Spectrometry</term>
<term>Models, Molecular</term>
<term>Piperidines (chemical synthesis)</term>
<term>Piperidines (chemistry)</term>
<term>Piperidines (metabolism)</term>
<term>Piperidines (pharmacology)</term>
<term>SARS Virus (enzymology)</term>
<term>Severe Acute Respiratory Syndrome (drug therapy)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Structure-Activity Relationship</term>
<term>Vero Cells</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
<term>Viral Proteins (chemistry)</term>
<term>Viral Proteins (metabolism)</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antienzymes ()</term>
<term>Antienzymes (métabolisme)</term>
<term>Antienzymes (pharmacologie)</term>
<term>Antienzymes (synthèse chimique)</term>
<term>Antiviraux ()</term>
<term>Antiviraux (métabolisme)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Cellules Vero</term>
<term>Concentration inhibitrice 50</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases ()</term>
<term>Cysteine endopeptidases (métabolisme)</term>
<term>Modèles moléculaires</term>
<term>Pipéridines ()</term>
<term>Pipéridines (métabolisme)</term>
<term>Pipéridines (pharmacologie)</term>
<term>Pipéridines (synthèse chimique)</term>
<term>Protéines virales ()</term>
<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Protéines virales (métabolisme)</term>
<term>Relation structure-activité</term>
<term>Réplication virale ()</term>
<term>Spectrométrie de masse</term>
<term>Spectroscopie par résonance magnétique</term>
<term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term>
<term>Syndrome respiratoire aigu sévère (virologie)</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>Enzyme Inhibitors</term>
<term>Piperidines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Cysteine Endopeptidases</term>
<term>Enzyme Inhibitors</term>
<term>Piperidines</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term>
<term>Cysteine Endopeptidases</term>
<term>Enzyme Inhibitors</term>
<term>Piperidines</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Enzyme Inhibitors</term>
<term>Piperidines</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>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</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="métabolisme" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Cysteine endopeptidases</term>
<term>Pipéridines</term>
<term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Pipéridines</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Pipéridines</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Inhibitory Concentration 50</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mass Spectrometry</term>
<term>Models, Molecular</term>
<term>Structure-Activity Relationship</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Antienzymes</term>
<term>Antiviraux</term>
<term>Cellules Vero</term>
<term>Concentration inhibitrice 50</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases</term>
<term>Modèles moléculaires</term>
<term>Pipéridines</term>
<term>Protéines virales</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Spectrométrie de masse</term>
<term>Spectroscopie par résonance magnétique</term>
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<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>
<double pmid="20527968"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation</title>
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<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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<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>
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<placeName><region type="state">Indiana</region>
</placeName>
<wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea>
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<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
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<placeName><region type="state">Illinois</region>
</placeName>
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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="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</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>
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<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>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation</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="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>
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<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>
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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>
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</affiliation>
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<author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</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="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>
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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="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name>
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</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>
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<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>
<pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.</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"><nlm:affiliation>Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907</wicri:regionArea>
<wicri:noRegion>Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
</author>
<author><name sortKey="Rao, Kalapala Venkateswara" sort="Rao, Kalapala Venkateswara" uniqKey="Rao K" first="Kalapala Venkateswara" last="Rao">Kalapala Venkateswara Rao</name>
</author>
<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
</author>
<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
</author>
<author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C" last="Mulhearn">Debbie C. Mulhearn</name>
</author>
<author><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name>
</author>
<author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B" last="Nichols">Daniel B. Nichols</name>
</author>
<author><name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name>
</author>
<author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name>
</author>
<author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E" last="Johnson">Michael E. Johnson</name>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PubMed</idno>
<date when="2010">2010</date>
<idno type="RBID">pubmed:20527968</idno>
<idno type="pmid">20527968</idno>
<idno type="doi">10.1021/jm1004489</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein-ligand X-ray structure and biological evaluation.</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"><nlm:affiliation>Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907</wicri:regionArea>
<wicri:noRegion>Indiana 47907</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
</author>
<author><name sortKey="Rao, Kalapala Venkateswara" sort="Rao, Kalapala Venkateswara" uniqKey="Rao K" first="Kalapala Venkateswara" last="Rao">Kalapala Venkateswara Rao</name>
</author>
<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
</author>
<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
</author>
<author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C" last="Mulhearn">Debbie C. Mulhearn</name>
</author>
<author><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name>
</author>
<author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B" last="Nichols">Daniel B. Nichols</name>
</author>
<author><name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name>
</author>
<author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name>
</author>
<author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E" last="Johnson">Michael E. Johnson</name>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name>
</author>
</analytic>
<series><title level="j">Journal of medicinal chemistry</title>
<idno type="eISSN">1520-4804</idno>
<imprint><date when="2010" type="published">2010</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
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<term>Antiviral Agents (chemical synthesis)</term>
<term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (metabolism)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Cysteine Endopeptidases (chemistry)</term>
<term>Cysteine Endopeptidases (metabolism)</term>
<term>Enzyme Inhibitors (chemical synthesis)</term>
<term>Enzyme Inhibitors (chemistry)</term>
<term>Enzyme Inhibitors (metabolism)</term>
<term>Enzyme Inhibitors (pharmacology)</term>
<term>Inhibitory Concentration 50</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mass Spectrometry</term>
<term>Models, Molecular</term>
<term>Piperidines (chemical synthesis)</term>
<term>Piperidines (chemistry)</term>
<term>Piperidines (metabolism)</term>
<term>Piperidines (pharmacology)</term>
<term>SARS Virus (enzymology)</term>
<term>Severe Acute Respiratory Syndrome (drug therapy)</term>
<term>Severe Acute Respiratory Syndrome (virology)</term>
<term>Structure-Activity Relationship</term>
<term>Vero Cells</term>
<term>Viral Proteins (antagonists & inhibitors)</term>
<term>Viral Proteins (chemistry)</term>
<term>Viral Proteins (metabolism)</term>
<term>Virus Replication (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antienzymes ()</term>
<term>Antienzymes (métabolisme)</term>
<term>Antienzymes (pharmacologie)</term>
<term>Antienzymes (synthèse chimique)</term>
<term>Antiviraux ()</term>
<term>Antiviraux (métabolisme)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Antiviraux (synthèse chimique)</term>
<term>Cellules Vero</term>
<term>Concentration inhibitrice 50</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases ()</term>
<term>Cysteine endopeptidases (métabolisme)</term>
<term>Modèles moléculaires</term>
<term>Pipéridines ()</term>
<term>Pipéridines (métabolisme)</term>
<term>Pipéridines (pharmacologie)</term>
<term>Pipéridines (synthèse chimique)</term>
<term>Protéines virales ()</term>
<term>Protéines virales (antagonistes et inhibiteurs)</term>
<term>Protéines virales (métabolisme)</term>
<term>Relation structure-activité</term>
<term>Réplication virale ()</term>
<term>Spectrométrie de masse</term>
<term>Spectroscopie par résonance magnétique</term>
<term>Syndrome respiratoire aigu sévère (traitement médicamenteux)</term>
<term>Syndrome respiratoire aigu sévère (virologie)</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>Enzyme Inhibitors</term>
<term>Piperidines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Cysteine Endopeptidases</term>
<term>Enzyme Inhibitors</term>
<term>Piperidines</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term>
<term>Cysteine Endopeptidases</term>
<term>Enzyme Inhibitors</term>
<term>Piperidines</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Enzyme Inhibitors</term>
<term>Piperidines</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>Virus Replication</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Severe Acute Respiratory Syndrome</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="métabolisme" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Cysteine endopeptidases</term>
<term>Pipéridines</term>
<term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Pipéridines</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antienzymes</term>
<term>Antiviraux</term>
<term>Pipéridines</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Severe Acute Respiratory Syndrome</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Chlorocebus aethiops</term>
<term>Crystallography, X-Ray</term>
<term>Inhibitory Concentration 50</term>
<term>Magnetic Resonance Spectroscopy</term>
<term>Mass Spectrometry</term>
<term>Models, Molecular</term>
<term>Structure-Activity Relationship</term>
<term>Vero Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Antienzymes</term>
<term>Antiviraux</term>
<term>Cellules Vero</term>
<term>Concentration inhibitrice 50</term>
<term>Cristallographie aux rayons X</term>
<term>Cysteine endopeptidases</term>
<term>Modèles moléculaires</term>
<term>Pipéridines</term>
<term>Protéines virales</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Spectrométrie de masse</term>
<term>Spectroscopie par résonance magnétique</term>
</keywords>
</textClass>
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</teiHeader>
<front><div type="abstract" xml:lang="en">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 3 (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 (S)-Me inhibitor 15 h (enzyme IC(50) = 0.56 microM; antiviral EC(50) = 9.1 microM) and the corresponding (R)-Me 15 g (IC(50) = 0.32 microM; antiviral EC(50) = 9.1 microM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15 g-bound SARS-CoV PLpro and a corresponding model of 15 h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.</div>
</front>
</TEI>
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