SrasV1, Main, Exploration, bibRecord, 002F06

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/Exploration ); précédent : 002F05; suivant : 002F07

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

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.

RBID : Pascal:09-0461730

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:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148848

Affiliations:

Le 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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<author><name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
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<author><name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</name>
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<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>
<affiliations><list><country><li>États-Unis</li>
</country>
<region><li>Illinois</li>
</region>
<settlement><li>Chicago</li>
</settlement>
<orgName><li>Université de Chicago</li>
<li>Université de l'Illinois à Chicago</li>
</orgName>
</list>
<tree><country name="États-Unis"><noRegion><name sortKey="Ghosh, Arun K" sort="Ghosh, Arun K" uniqKey="Ghosh A" first="Arun K." last="Ghosh">Arun K. Ghosh</name>
</noRegion>
<name sortKey="Aubin, Yoann" sort="Aubin, Yoann" uniqKey="Aubin Y" first="Yoann" last="Aubin">Yoann Aubin</name>
<name sortKey="Baez, Yahira" sort="Baez, Yahira" uniqKey="Baez Y" first="Yahira" last="Baez">Yahira Baez</name>
<name sortKey="Bakery, Susan C" sort="Bakery, Susan C" uniqKey="Bakery S" first="Susan C." last="Bakery">Susan C. Bakery</name>
<name sortKey="Chaudhuri, Rima" sort="Chaudhuri, Rima" uniqKey="Chaudhuri R" first="Rima" last="Chaudhuri">Rima Chaudhuri</name>
<name sortKey="Coughlin, Melissa" sort="Coughlin, Melissa" uniqKey="Coughlin M" first="Melissa" last="Coughlin">Melissa Coughlin</name>
<name sortKey="Johnson, Michael E" sort="Johnson, Michael E" uniqKey="Johnson M" first="Michael E." last="Johnson">Michael E. Johnson</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="Prabhakar, Bellur S" sort="Prabhakar, Bellur S" uniqKey="Prabhakar B" first="Bellur S." last="Prabhakar">Bellur S. Prabhakar</name>
<name sortKey="Ratia, Kiira" sort="Ratia, Kiira" uniqKey="Ratia K" first="Kiira" last="Ratia">Kiira Ratia</name>
<name sortKey="Sleeman, Katrina" sort="Sleeman, Katrina" uniqKey="Sleeman K" first="Katrina" last="Sleeman">Katrina Sleeman</name>
<name sortKey="Takayama, Jun" sort="Takayama, Jun" uniqKey="Takayama J" first="Jun" last="Takayama">Jun Takayama</name>
</country>
</tree>
</affiliations>
</record>

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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

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

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