Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes
Identifieur interne : 000E24 ( Main/Exploration ); précédent : 000E23; suivant : 000E25Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes
Auteurs : Min-Han Lin [Taïwan] ; David C. Moses [Taïwan] ; Chih-Hua Hsieh [Taïwan] ; Shu-Chun Cheng [Taïwan] ; Yau-Hung Chen [Taïwan] ; Chiao-Yin Sun [Taïwan] ; Chi-Yuan Chou [Taïwan]Source :
- Antiviral Research [ 0166-3542 ] ; 2017.
Descripteurs français
- KwdFr :
- Activation enzymatique (), Antiviraux (pharmacologie), Concentration inhibitrice 50, Conformation moléculaire, Coronavirus du syndrome respiratoire du Moyen-Orient (), Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie), Coronavirus du syndrome respiratoire du Moyen-Orient (génétique), Disulfirame (), Disulfirame (pharmacologie), Humains, Liaison aux protéines, Modèles moléculaires, Peptide hydrolases (), Peptide hydrolases (génétique), Peptide hydrolases (métabolisme), Relation dose-effet des médicaments, Tests de sensibilité microbienne, Virus du SRAS (), Virus du SRAS (enzymologie), Virus du SRAS (génétique).
- MESH :
- enzymologie : Coronavirus du syndrome respiratoire du Moyen-Orient, Virus du SRAS.
- génétique : Coronavirus du syndrome respiratoire du Moyen-Orient, Peptide hydrolases, Virus du SRAS.
- métabolisme : Peptide hydrolases.
- pharmacologie : Antiviraux, Disulfirame.
- Activation enzymatique, Concentration inhibitrice 50, Conformation moléculaire, Coronavirus du syndrome respiratoire du Moyen-Orient, Disulfirame, Humains, Liaison aux protéines, Modèles moléculaires, Peptide hydrolases, Relation dose-effet des médicaments, Tests de sensibilité microbienne, Virus du SRAS.
English descriptors
- KwdEn :
- Antiviral Agents (pharmacology), Disulfiram (chemistry), Disulfiram (pharmacology), Dose-Response Relationship, Drug, Enzyme Activation (drug effects), Humans, Inhibitory Concentration 50, Microbial Sensitivity Tests, Middle East Respiratory Syndrome Coronavirus (drug effects), Middle East Respiratory Syndrome Coronavirus (enzymology), Middle East Respiratory Syndrome Coronavirus (genetics), Models, Molecular, Molecular Conformation, Peptide Hydrolases (chemistry), Peptide Hydrolases (genetics), Peptide Hydrolases (metabolism), Protein Binding, SARS Virus (drug effects), SARS Virus (enzymology), SARS Virus (genetics).
- MESH :
- chemical , chemistry : Disulfiram, Peptide Hydrolases.
- chemical , genetics : Peptide Hydrolases.
- chemical , metabolism : Peptide Hydrolases.
- chemical , pharmacology : Antiviral Agents, Disulfiram.
- drug effects : Enzyme Activation, Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- enzymology : Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- genetics : Middle East Respiratory Syndrome Coronavirus, SARS Virus.
- Dose-Response Relationship, Drug, Humans, Inhibitory Concentration 50, Microbial Sensitivity Tests, Models, Molecular, Molecular Conformation, Protein Binding.
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV. Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PLpros) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PLpro but as a competitive (or mixed) inhibitor of SARS-CoV PLpro. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PLpro by disulfiram, while synergistic inhibition of MERS-CoV PLpro by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.
Url:
DOI: 10.1016/j.antiviral.2017.12.015
PubMed: 29289665
PubMed Central: 7113793
Affiliations:
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Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112</wicri:regionArea><wicri:noRegion>Taipei 112</wicri:noRegion></affiliation></author><author><name sortKey="Moses, David C" sort="Moses, David C" uniqKey="Moses D" first="David C." last="Moses">David C. Moses</name><affiliation wicri:level="1"><nlm:aff id="aff2">Department of Chemistry, Tamkang University, Tamsui 251, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Chemistry, Tamkang University, Tamsui 251</wicri:regionArea><wicri:noRegion>Tamsui 251</wicri:noRegion></affiliation></author><author><name sortKey="Hsieh, Chih Hua" sort="Hsieh, Chih Hua" uniqKey="Hsieh C" first="Chih-Hua" last="Hsieh">Chih-Hua Hsieh</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112</wicri:regionArea><wicri:noRegion>Taipei 112</wicri:noRegion></affiliation></author><author><name sortKey="Cheng, Shu Chun" sort="Cheng, Shu Chun" uniqKey="Cheng S" first="Shu-Chun" last="Cheng">Shu-Chun Cheng</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204</wicri:regionArea><wicri:noRegion>Keelung 204</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Yau Hung" sort="Chen, Yau Hung" uniqKey="Chen Y" first="Yau-Hung" last="Chen">Yau-Hung Chen</name><affiliation wicri:level="1"><nlm:aff id="aff2">Department of Chemistry, Tamkang University, Tamsui 251, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Chemistry, Tamkang University, Tamsui 251</wicri:regionArea><wicri:noRegion>Tamsui 251</wicri:noRegion></affiliation></author><author><name sortKey="Sun, Chiao Yin" sort="Sun, Chiao Yin" uniqKey="Sun C" first="Chiao-Yin" last="Sun">Chiao-Yin Sun</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Nephrology, Chang-Gung Memorial Hospital, Keelung 204</wicri:regionArea><wicri:noRegion>Keelung 204</wicri:noRegion></affiliation></author><author><name sortKey="Chou, Chi Yuan" sort="Chou, Chi Yuan" uniqKey="Chou C" first="Chi-Yuan" last="Chou">Chi-Yuan Chou</name><affiliation wicri:level="1"><nlm:aff id="aff1">Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112</wicri:regionArea><wicri:noRegion>Taipei 112</wicri:noRegion></affiliation></author></analytic><series><title level="j">Antiviral Research</title><idno type="ISSN">0166-3542</idno><idno type="eISSN">1872-9096</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antiviral Agents (pharmacology)</term><term>Disulfiram (chemistry)</term><term>Disulfiram (pharmacology)</term><term>Dose-Response Relationship, Drug</term><term>Enzyme Activation (drug effects)</term><term>Humans</term><term>Inhibitory Concentration 50</term><term>Microbial Sensitivity Tests</term><term>Middle East Respiratory Syndrome Coronavirus (drug effects)</term><term>Middle East Respiratory Syndrome Coronavirus (enzymology)</term><term>Middle East Respiratory Syndrome Coronavirus (genetics)</term><term>Models, Molecular</term><term>Molecular Conformation</term><term>Peptide Hydrolases (chemistry)</term><term>Peptide Hydrolases (genetics)</term><term>Peptide Hydrolases (metabolism)</term><term>Protein Binding</term><term>SARS Virus (drug effects)</term><term>SARS Virus (enzymology)</term><term>SARS Virus (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation enzymatique ()</term><term>Antiviraux (pharmacologie)</term><term>Concentration inhibitrice 50</term><term>Conformation moléculaire</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient ()</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (enzymologie)</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient (génétique)</term><term>Disulfirame ()</term><term>Disulfirame (pharmacologie)</term><term>Humains</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Peptide hydrolases ()</term><term>Peptide hydrolases (génétique)</term><term>Peptide hydrolases (métabolisme)</term><term>Relation dose-effet des médicaments</term><term>Tests de sensibilité microbienne</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term><term>Virus du SRAS (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Disulfiram</term><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Disulfiram</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Enzyme Activation</term><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Middle East Respiratory Syndrome Coronavirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Peptide hydrolases</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Peptide hydrolases</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Disulfirame</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term><term>Humans</term><term>Inhibitory Concentration 50</term><term>Microbial Sensitivity Tests</term><term>Models, Molecular</term><term>Molecular Conformation</term><term>Protein Binding</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation enzymatique</term><term>Concentration inhibitrice 50</term><term>Conformation moléculaire</term><term>Coronavirus du syndrome respiratoire du Moyen-Orient</term><term>Disulfirame</term><term>Humains</term><term>Liaison aux protéines</term><term>Modèles moléculaires</term><term>Peptide hydrolases</term><term>Relation dose-effet des médicaments</term><term>Tests de sensibilité microbienne</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in southern China in late 2002 and caused a global outbreak with a fatality rate around 10% in 2003. Ten years later, a second highly pathogenic human CoV, MERS-CoV, emerged in the Middle East and has spread to other countries in Europe, North Africa, North America and Asia. As of November 2017, MERS-CoV had infected at least 2102 people with a fatality rate of about 35% globally, and hence there is an urgent need to identify antiviral drugs that are active against MERS-CoV. Here we show that a clinically available alcohol-aversive drug, disulfiram, can inhibit the papain-like proteases (PL<sup>pro</sup>s) of MERS-CoV and SARS-CoV. Our findings suggest that disulfiram acts as an allosteric inhibitor of MERS-CoV PL<sup>pro</sup> but as a competitive (or mixed) inhibitor of SARS-CoV PL<sup>pro</sup>. The phenomenon of slow-binding inhibition and the irrecoverability of enzyme activity after removing unbound disulfiram indicate covalent inactivation of SARS-CoV PL<sup>pro</sup> by disulfiram, while synergistic inhibition of MERS-CoV PL<sup>pro</sup> by disulfiram and 6-thioguanine or mycophenolic acid implies the potential for combination treatments using these three clinically available drugs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bailey Elkin, B A" uniqKey="Bailey Elkin B">B.A. Bailey-Elkin</name></author><author><name sortKey="Knaap, R C" uniqKey="Knaap R">R.C. Knaap</name></author><author><name sortKey="Johnson, G G" uniqKey="Johnson G">G.G. Johnson</name></author><author><name sortKey="Dalebout, T J" uniqKey="Dalebout T">T.J. Dalebout</name></author><author><name sortKey="Ninaber, D K" uniqKey="Ninaber D">D.K. 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Tang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Taïwan</li></country></list><tree><country name="Taïwan"><noRegion><name sortKey="Lin, Min Han" sort="Lin, Min Han" uniqKey="Lin M" first="Min-Han" last="Lin">Min-Han Lin</name></noRegion><name sortKey="Chen, Yau Hung" sort="Chen, Yau Hung" uniqKey="Chen Y" first="Yau-Hung" last="Chen">Yau-Hung Chen</name><name sortKey="Cheng, Shu Chun" sort="Cheng, Shu Chun" uniqKey="Cheng S" first="Shu-Chun" last="Cheng">Shu-Chun Cheng</name><name sortKey="Chou, Chi Yuan" sort="Chou, Chi Yuan" uniqKey="Chou C" first="Chi-Yuan" last="Chou">Chi-Yuan Chou</name><name sortKey="Hsieh, Chih Hua" sort="Hsieh, Chih Hua" uniqKey="Hsieh C" first="Chih-Hua" last="Hsieh">Chih-Hua Hsieh</name><name sortKey="Moses, David C" sort="Moses, David C" uniqKey="Moses D" first="David C." last="Moses">David C. 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HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:29289665" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a MersV1
| This area was generated with Dilib version V0.6.33. |  |