SrasV1, Main, Exploration, bibRecord, 002450

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Identifieur interne : 002450 ( Main/Exploration ); précédent : 002449; suivant : 002451

Severe 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.

RBID : PMC:2918394

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 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 15h (enzyme IC₅₀ = 0.56 μM; antiviral EC₅₀ = 9.1 μM) and the corresponding (R)-Me 15g (IC₅₀ = 0.32 μM; antiviral EC₅₀ = 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 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918394

DOI: 10.1021/jm1004489
PubMed: 20527968
PubMed Central: 2918394

Affiliations:

Le document en format XML

<record><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="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Indiana</region>
</placeName>
<wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
<affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Indiana</region>
</placeName>
<wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Rao, Kalapala Venkateswara" sort="Rao, Kalapala Venkateswara" uniqKey="Rao K" first="Kalapala Venkateswara" last="Rao">Kalapala Venkateswara Rao</name>
<affiliation wicri:level="2"><nlm:aff id="A1">Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Indiana</region>
</placeName>
<wicri:cityArea>Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B." last="Nichols">Daniel B. Nichols</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C." last="Baker">Susan C. Baker</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">20527968</idno>
<idno type="pmc">2918394</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918394</idno>
<idno type="RBID">PMC:2918394</idno>
<idno type="doi">10.1021/jm1004489</idno>
<date when="2010">2010</date>
<idno type="wicri:Area/Pmc/Corpus">000C17</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C17</idno>
<idno type="wicri:Area/Pmc/Curation">000C17</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000C17</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000B89</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000B89</idno>
<idno type="wicri:source">PubMed</idno>
<idno type="RBID">pubmed:20527968</idno>
<idno type="wicri:Area/PubMed/Corpus">001686</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001686</idno>
<idno type="wicri:Area/PubMed/Curation">001686</idno>
<idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001686</idno>
<idno type="wicri:Area/PubMed/Checkpoint">001592</idno>
<idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001592</idno>
<idno type="wicri:Area/Ncbi/Merge">002151</idno>
<idno type="wicri:Area/Ncbi/Curation">002151</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">002151</idno>
<idno type="wicri:doubleKey">0022-2623:2010:Ghosh A:severe:acute:respiratory</idno>
<idno type="wicri:Area/Main/Merge">002483</idno>
<idno type="wicri:Area/Main/Curation">002450</idno>
<idno type="wicri:Area/Main/Exploration">002450</idno>
</publicationStmt>
<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>
</author>
<author><name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B." last="Nichols">Daniel B. Nichols</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C." last="Baker">Susan C. Baker</name>
<affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Department of Microbiology and Immunology, Loyola University of Chicago, Stritch School of Medicine, Maywood</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name>
<affiliation wicri:level="2"><nlm:aff id="A2">Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland, IL</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Illinois</region>
</placeName>
<wicri:cityArea>Center for Pharmaceutical Biotechnology and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S. Ashland</wicri:cityArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of medicinal chemistry</title>
<idno type="ISSN">0022-2623</idno>
<idno type="eISSN">1520-4804</idno>
<imprint><date when="2010">2010</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><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>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="P1">The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound <bold>3</bold>
 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (<italic>S</italic>
)-Me inhibitor <bold>15h</bold>
 (enzyme IC<sub>50</sub>
 = 0.56 μM; antiviral EC<sub>50</sub>
 = 9.1 μM) and the corresponding (<italic>R</italic>
)-Me <bold>15g</bold>
 (IC<sub>50</sub>
 = 0.32 μM; antiviral EC<sub>50</sub>
 = 9.1 μM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of <bold>15g</bold>
-bound SARS-CoV PLpro and a corresponding model of <bold>15h</bold>
 docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Illinois</li>
<li>Indiana</li>
</region>
</list>
<tree><country name="États-Unis"><region name="Indiana"><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name>
</region>
<name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C." last="Baker">Susan C. Baker</name>
<name sortKey="Baliji, Surendranath" sort="Baliji, Surendranath" uniqKey="Baliji S" first="Surendranath" last="Baliji">Surendranath Baliji</name>
<name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
<name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</name>
<name sortKey="Lee, Hyun" sort="Lee, Hyun" uniqKey="Lee H" first="Hyun" last="Lee">Hyun Lee</name>
<name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D." last="Mesecar">Andrew D. Mesecar</name>
<name sortKey="Mulhearn, Debbie C" sort="Mulhearn, Debbie C" uniqKey="Mulhearn D" first="Debbie C." last="Mulhearn">Debbie C. Mulhearn</name>
<name sortKey="Nichols, Daniel B" sort="Nichols, Daniel B" uniqKey="Nichols D" first="Daniel B." last="Nichols">Daniel B. Nichols</name>
<name sortKey="Rao, Kalapala Venkateswara" sort="Rao, Kalapala Venkateswara" uniqKey="Rao K" first="Kalapala Venkateswara" last="Rao">Kalapala Venkateswara Rao</name>
<name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
<name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
</country>
</tree>
</affiliations>
</record>

Pour manipuler ce document sous Unix (Dilib)

EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Main/Exploration

HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 002450 | SxmlIndent | more

HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 002450 | SxmlIndent | more

Pour mettre un lien sur cette page dans le réseau Wicri

{{Explor lien
   |wiki=    Sante
   |area=    SrasV1
   |flux=    Main
   |étape=   Exploration
   |type=    RBID
   |clé=     PMC:2918394
   |texte=   Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:20527968" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a SrasV1

This area was generated with Dilib version V0.6.33.
Data generation: Tue Apr 28 14:49:16 2020. Site generation: Sat Mar 27 22:06:49 2021

Serveur d'exploration SRAS

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation

Source :

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki

	Serveur d'exploration SRAS
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.