X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases.
Identifieur interne : 001530 ( Main/Exploration ); précédent : 001529; suivant : 001531X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases.
Auteurs : Yahira M. Báez-Santos [États-Unis] ; Scott J. Barraza ; Michael W. Wilson ; Michael P. Agius ; Anna M. Mielech ; Nicole M. Davis ; Susan C. Baker ; Scott D. Larsen ; Andrew D. MesecarSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (métabolisme), Antiviraux (pharmacologie), Antiviraux (synthèse chimique), Cellules Vero, Conformation moléculaire, Coronavirus (), Coronavirus (enzymologie), Diffraction des rayons X, Humains, Indicateurs et réactifs, Inhibiteurs de la cystéine protéinase (pharmacologie), Inhibiteurs de la cystéine protéinase (synthèse chimique), Inhibiteurs de la phospholipase A2 (pharmacologie), Inhibiteurs de la phospholipase A2 (synthèse chimique), Liaison aux protéines, Mutagenèse (), Papaïne (), Peptide hydrolases (), Peptide hydrolases (métabolisme), Relation structure-activité, Survie cellulaire (), Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- enzymologie : Coronavirus, Virus du SRAS.
- métabolisme : Antiviraux, Peptide hydrolases.
- pharmacologie : Antiviraux, Inhibiteurs de la cystéine protéinase, Inhibiteurs de la phospholipase A2.
- synthèse chimique : Antiviraux, Inhibiteurs de la cystéine protéinase, Inhibiteurs de la phospholipase A2.
- Animaux, Cellules Vero, Conformation moléculaire, Coronavirus, Diffraction des rayons X, Humains, Indicateurs et réactifs, Liaison aux protéines, Mutagenèse, Papaïne, Peptide hydrolases, Relation structure-activité, Survie cellulaire, Virus du SRAS.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (chemical synthesis), Antiviral Agents (metabolism), Antiviral Agents (pharmacology), Cell Survival (drug effects), Chlorocebus aethiops, Coronavirus (drug effects), Coronavirus (enzymology), Cysteine Proteinase Inhibitors (chemical synthesis), Cysteine Proteinase Inhibitors (pharmacology), Humans, Indicators and Reagents, Molecular Conformation, Mutagenesis (drug effects), Papain (chemistry), Peptide Hydrolases (chemistry), Peptide Hydrolases (metabolism), Phospholipase A2 Inhibitors (chemical synthesis), Phospholipase A2 Inhibitors (pharmacology), Protein Binding, SARS Virus (drug effects), SARS Virus (enzymology), Structure-Activity Relationship, Vero Cells, X-Ray Diffraction.
- MESH :
- chemical , chemical synthesis : Antiviral Agents, Cysteine Proteinase Inhibitors, Phospholipase A2 Inhibitors.
- chemical , chemistry : Papain, Peptide Hydrolases.
- chemical , metabolism : Antiviral Agents, Peptide Hydrolases.
- chemical , pharmacology : Antiviral Agents, Cysteine Proteinase Inhibitors, Phospholipase A2 Inhibitors.
- drug effects : Cell Survival, Coronavirus, Mutagenesis, SARS Virus.
- enzymology : Coronavirus, SARS Virus.
- Animals, Chlorocebus aethiops, Humans, Indicators and Reagents, Molecular Conformation, Protein Binding, Structure-Activity Relationship, Vero Cells, X-Ray Diffraction.
Abstract
Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.
DOI: 10.1021/jm401712t
PubMed: 24568342
Affiliations:
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Barraza</name></author><author><name sortKey="Wilson, Michael W" sort="Wilson, Michael W" uniqKey="Wilson M" first="Michael W" last="Wilson">Michael W. Wilson</name></author><author><name sortKey="Agius, Michael P" sort="Agius, Michael P" uniqKey="Agius M" first="Michael P" last="Agius">Michael P. Agius</name></author><author><name sortKey="Mielech, Anna M" sort="Mielech, Anna M" uniqKey="Mielech A" first="Anna M" last="Mielech">Anna M. Mielech</name></author><author><name sortKey="Davis, Nicole M" sort="Davis, Nicole M" uniqKey="Davis N" first="Nicole M" last="Davis">Nicole M. Davis</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="Larsen, Scott D" sort="Larsen, Scott D" uniqKey="Larsen S" first="Scott D" last="Larsen">Scott D. 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Báez-Santos</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biological Sciences, Purdue University , 915 W. State Street, West Lafayette, Indiana 47907, United States.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biological Sciences, Purdue University , 915 W. State Street, West Lafayette, Indiana 47907</wicri:regionArea><wicri:noRegion>Indiana 47907</wicri:noRegion></affiliation></author><author><name sortKey="Barraza, Scott J" sort="Barraza, Scott J" uniqKey="Barraza S" first="Scott J" last="Barraza">Scott J. Barraza</name></author><author><name sortKey="Wilson, Michael W" sort="Wilson, Michael W" uniqKey="Wilson M" first="Michael W" last="Wilson">Michael W. Wilson</name></author><author><name sortKey="Agius, Michael P" sort="Agius, Michael P" uniqKey="Agius M" first="Michael P" last="Agius">Michael P. 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Mesecar</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2014" type="published">2014</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 (metabolism)</term><term>Antiviral Agents (pharmacology)</term><term>Cell Survival (drug effects)</term><term>Chlorocebus aethiops</term><term>Coronavirus (drug effects)</term><term>Coronavirus (enzymology)</term><term>Cysteine Proteinase Inhibitors (chemical synthesis)</term><term>Cysteine Proteinase Inhibitors (pharmacology)</term><term>Humans</term><term>Indicators and Reagents</term><term>Molecular Conformation</term><term>Mutagenesis (drug effects)</term><term>Papain (chemistry)</term><term>Peptide Hydrolases (chemistry)</term><term>Peptide Hydrolases (metabolism)</term><term>Phospholipase A2 Inhibitors (chemical synthesis)</term><term>Phospholipase A2 Inhibitors (pharmacology)</term><term>Protein Binding</term><term>SARS Virus (drug effects)</term><term>SARS Virus (enzymology)</term><term>Structure-Activity Relationship</term><term>Vero Cells</term><term>X-Ray Diffraction</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux (métabolisme)</term><term>Antiviraux (pharmacologie)</term><term>Antiviraux (synthèse chimique)</term><term>Cellules Vero</term><term>Conformation moléculaire</term><term>Coronavirus ()</term><term>Coronavirus (enzymologie)</term><term>Diffraction des rayons X</term><term>Humains</term><term>Indicateurs et réactifs</term><term>Inhibiteurs de la cystéine protéinase (pharmacologie)</term><term>Inhibiteurs de la cystéine protéinase (synthèse chimique)</term><term>Inhibiteurs de la phospholipase A2 (pharmacologie)</term><term>Inhibiteurs de la phospholipase A2 (synthèse chimique)</term><term>Liaison aux protéines</term><term>Mutagenèse ()</term><term>Papaïne ()</term><term>Peptide hydrolases ()</term><term>Peptide hydrolases (métabolisme)</term><term>Relation structure-activité</term><term>Survie cellulaire ()</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Proteinase Inhibitors</term><term>Phospholipase A2 Inhibitors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Papain</term><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antiviral Agents</term><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Cysteine Proteinase Inhibitors</term><term>Phospholipase A2 Inhibitors</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Survival</term><term>Coronavirus</term><term>Mutagenesis</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antiviraux</term><term>Peptide hydrolases</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Inhibiteurs de la cystéine protéinase</term><term>Inhibiteurs de la phospholipase A2</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Antiviraux</term><term>Inhibiteurs de la cystéine protéinase</term><term>Inhibiteurs de la phospholipase A2</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Chlorocebus aethiops</term><term>Humans</term><term>Indicators and Reagents</term><term>Molecular Conformation</term><term>Protein Binding</term><term>Structure-Activity Relationship</term><term>Vero Cells</term><term>X-Ray Diffraction</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules Vero</term><term>Conformation moléculaire</term><term>Coronavirus</term><term>Diffraction des rayons X</term><term>Humains</term><term>Indicateurs et réactifs</term><term>Liaison aux protéines</term><term>Mutagenèse</term><term>Papaïne</term><term>Peptide hydrolases</term><term>Relation structure-activité</term><term>Survie cellulaire</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Agius, Michael P" sort="Agius, Michael P" uniqKey="Agius M" first="Michael P" last="Agius">Michael P. Agius</name><name sortKey="Baker, Susan C" sort="Baker, Susan C" uniqKey="Baker S" first="Susan C" last="Baker">Susan C. Baker</name><name sortKey="Barraza, Scott J" sort="Barraza, Scott J" uniqKey="Barraza S" first="Scott J" last="Barraza">Scott J. Barraza</name><name sortKey="Davis, Nicole M" sort="Davis, Nicole M" uniqKey="Davis N" first="Nicole M" last="Davis">Nicole M. Davis</name><name sortKey="Larsen, Scott D" sort="Larsen, Scott D" uniqKey="Larsen S" first="Scott D" last="Larsen">Scott D. Larsen</name><name sortKey="Mesecar, Andrew D" sort="Mesecar, Andrew D" uniqKey="Mesecar A" first="Andrew D" last="Mesecar">Andrew D. Mesecar</name><name sortKey="Mielech, Anna M" sort="Mielech, Anna M" uniqKey="Mielech A" first="Anna M" last="Mielech">Anna M. Mielech</name><name sortKey="Wilson, Michael W" sort="Wilson, Michael W" uniqKey="Wilson M" first="Michael W" last="Wilson">Michael W. Wilson</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Baez Santos, Yahira M" sort="Baez Santos, Yahira M" uniqKey="Baez Santos Y" first="Yahira M" last="Báez-Santos">Yahira M. Báez-Santos</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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