Targeting Coronaviral Replication and Cellular JAK2 Mediated Dominant NF-κB Activation for Comprehensive and Ultimate Inhibition of Coronaviral Activity
Identifieur interne : 000B68 ( Main/Merge ); précédent : 000B67; suivant : 000B69Targeting Coronaviral Replication and Cellular JAK2 Mediated Dominant NF-κB Activation for Comprehensive and Ultimate Inhibition of Coronaviral Activity
Auteurs : Cheng-Wei Yang [République populaire de Chine] ; Yue-Zhi Lee [République populaire de Chine] ; Hsing-Yu Hsu [République populaire de Chine] ; Chuan Shih [République populaire de Chine] ; Yu-Sheng Chao [République populaire de Chine] ; Hwan-You Chang [République populaire de Chine] ; Shiow-Ju Lee [République populaire de Chine]Source :
- Scientific Reports [ 2045-2322 ] ; 2017.
Descripteurs français
- KwdFr :
- ARN viral, Alcaloïdes (), Alcaloïdes (pharmacologie), Antiviraux (), Antiviraux (pharmacologie), Benzamides (pharmacologie), Coronavirus (), Coronavirus (physiologie), Facteur de transcription NF-kappa B (métabolisme), Indolizine (), Indolizine (pharmacologie), Infections à coronavirus (métabolisme), Infections à coronavirus (traitement médicamenteux), Infections à coronavirus (virologie), Interactions hôte-pathogène, Kinase Janus-2 (métabolisme), Modèles biologiques, Phosphorylation, Phénanthrènes (), Phénanthrènes (pharmacologie), Réplication virale (), Transcription génétique, Transduction du signal ().
- MESH :
- métabolisme : Facteur de transcription NF-kappa B, Infections à coronavirus, Kinase Janus-2.
- pharmacologie : Alcaloïdes, Antiviraux, Benzamides, Indolizine, Phénanthrènes.
- physiologie : Coronavirus.
- traitement médicamenteux : Infections à coronavirus.
- virologie : Infections à coronavirus.
- ARN viral, Alcaloïdes, Antiviraux, Coronavirus, Indolizine, Interactions hôte-pathogène, Modèles biologiques, Phosphorylation, Phénanthrènes, Réplication virale, Transcription génétique, Transduction du signal.
English descriptors
- KwdEn :
- Alkaloids (chemistry), Alkaloids (pharmacology), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Benzamides (pharmacology), Coronavirus (drug effects), Coronavirus (physiology), Coronavirus Infections (drug therapy), Coronavirus Infections (metabolism), Coronavirus Infections (virology), Host-Pathogen Interactions, Indolizines (chemistry), Indolizines (pharmacology), Janus Kinase 2 (metabolism), Models, Biological, NF-kappa B (metabolism), Phenanthrenes (chemistry), Phenanthrenes (pharmacology), Phosphorylation, RNA, Viral, Signal Transduction (drug effects), Transcription, Genetic, Virus Replication (drug effects).
- MESH :
- chemical , chemistry : Alkaloids, Antiviral Agents, Indolizines, Phenanthrenes.
- chemical , metabolism : Janus Kinase 2, NF-kappa B.
- chemical , pharmacology : Alkaloids, Antiviral Agents, Benzamides, Indolizines, Phenanthrenes.
- drug effects : Coronavirus, Signal Transduction, Virus Replication.
- drug therapy : Coronavirus Infections.
- metabolism : Coronavirus Infections.
- physiology : Coronavirus.
- virology : Coronavirus Infections.
- Host-Pathogen Interactions, Models, Biological, Phosphorylation, RNA, Viral, Transcription, Genetic.
Abstract
Tylophorine-based compounds exert broad spectral, potent inhibition of coronaviruses. NF-κB activation is a common pro-inflammatory response of host cells to viral infection. The aims of this study were to (i) find an effective combination treatment for coronaviral infections through targeting of the virus per se and cellular NF-κB activity; and (ii) to study the underling mechanisms. We found that tylophorine-based compounds target the TGEV viral RNA and effectively inhibit TGEV replication. NF-κB inhibition also leads to anti-TGEV replication. NF-κB activation induced by TGEV infection was found to be associated with two convergent pathways, IKK-2_IκBα/p65 and JAK2 mediated p65 phosphorylation, in swine testicular cells. JAK2 inhibition either by CYT387 (a JAK family inhibitor) or by silencing JAK2-expression revealed a dominant JAK2 mediated p65 phosphorylation pathway for NF-κB activation and resulted in NF-κB inhibition, which overrode the IκBα regulation via the IKK-2. Finally, tylophorine-based compounds work cooperatively with CYT387 to impart comprehensive anti-TGEV activities. The combination treatment, wherein a tylophorine compound targets TGEV and a JAK2 inhibitor blocks the alternative dominant NF-κB activation mediated by JAK2, is more effective and comprehensive than either one alone and constitutes a feasible approach for the treatment of SARS-CoV or MERS-CoV.
Url:
DOI: 10.1038/s41598-017-04203-9
PubMed: 28642467
PubMed Central: 5481340
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PMC:5481340Le document en format XML
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id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000000406229172</institution-id><institution-id institution-id-type="GRID">grid.59784.37</institution-id><institution>Institute of Biotechnology and Pharmaceutical Research,</institution><institution>National Health Research Institutes,</institution></institution-wrap>Miaoli, 35053 Taiwan, ROC</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Miaoli, 35053 Taiwan</wicri:regionArea><wicri:noRegion>35053 Taiwan</wicri:noRegion></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Alkaloids (chemistry)</term><term>Alkaloids (pharmacology)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Benzamides (pharmacology)</term><term>Coronavirus (drug effects)</term><term>Coronavirus (physiology)</term><term>Coronavirus Infections (drug therapy)</term><term>Coronavirus Infections (metabolism)</term><term>Coronavirus Infections (virology)</term><term>Host-Pathogen Interactions</term><term>Indolizines (chemistry)</term><term>Indolizines (pharmacology)</term><term>Janus Kinase 2 (metabolism)</term><term>Models, Biological</term><term>NF-kappa B (metabolism)</term><term>Phenanthrenes (chemistry)</term><term>Phenanthrenes (pharmacology)</term><term>Phosphorylation</term><term>RNA, Viral</term><term>Signal Transduction (drug effects)</term><term>Transcription, Genetic</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN viral</term><term>Alcaloïdes ()</term><term>Alcaloïdes (pharmacologie)</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Benzamides (pharmacologie)</term><term>Coronavirus ()</term><term>Coronavirus (physiologie)</term><term>Facteur de transcription NF-kappa B (métabolisme)</term><term>Indolizine ()</term><term>Indolizine (pharmacologie)</term><term>Infections à coronavirus (métabolisme)</term><term>Infections à coronavirus (traitement médicamenteux)</term><term>Infections à coronavirus (virologie)</term><term>Interactions hôte-pathogène</term><term>Kinase Janus-2 (métabolisme)</term><term>Modèles biologiques</term><term>Phosphorylation</term><term>Phénanthrènes ()</term><term>Phénanthrènes (pharmacologie)</term><term>Réplication virale ()</term><term>Transcription génétique</term><term>Transduction du signal ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Alkaloids</term><term>Antiviral Agents</term><term>Indolizines</term><term>Phenanthrenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Janus Kinase 2</term><term>NF-kappa B</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Alkaloids</term><term>Antiviral Agents</term><term>Benzamides</term><term>Indolizines</term><term>Phenanthrenes</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term><term>Signal Transduction</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur de transcription NF-kappa B</term><term>Infections à coronavirus</term><term>Kinase Janus-2</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Alcaloïdes</term><term>Antiviraux</term><term>Benzamides</term><term>Indolizine</term><term>Phénanthrènes</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Host-Pathogen Interactions</term><term>Models, Biological</term><term>Phosphorylation</term><term>RNA, Viral</term><term>Transcription, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ARN viral</term><term>Alcaloïdes</term><term>Antiviraux</term><term>Coronavirus</term><term>Indolizine</term><term>Interactions hôte-pathogène</term><term>Modèles biologiques</term><term>Phosphorylation</term><term>Phénanthrènes</term><term>Réplication virale</term><term>Transcription génétique</term><term>Transduction du signal</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Tylophorine-based compounds exert broad spectral, potent inhibition of coronaviruses. NF-κB activation is a common pro-inflammatory response of host cells to viral infection. The aims of this study were to (i) find an effective combination treatment for coronaviral infections through targeting of the virus per se and cellular NF-κB activity; and (ii) to study the underling mechanisms. We found that tylophorine-based compounds target the TGEV viral RNA and effectively inhibit TGEV replication. NF-κB inhibition also leads to anti-TGEV replication. NF-κB activation induced by TGEV infection was found to be associated with two convergent pathways, IKK-2_IκBα/p65 and JAK2 mediated p65 phosphorylation, in swine testicular cells. JAK2 inhibition either by CYT387 (a JAK family inhibitor) or by silencing JAK2-expression revealed a dominant JAK2 mediated p65 phosphorylation pathway for NF-κB activation and resulted in NF-κB inhibition, which overrode the IκBα regulation via the IKK-2. Finally, tylophorine-based compounds work cooperatively with CYT387 to impart comprehensive anti-TGEV activities. The combination treatment, wherein a tylophorine compound targets TGEV and a JAK2 inhibitor blocks the alternative dominant NF-κB activation mediated by JAK2, is more effective and comprehensive than either one alone and constitutes a feasible approach for the treatment of SARS-CoV or MERS-CoV.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Weiss, Sr" uniqKey="Weiss S">SR Weiss</name></author><author><name sortKey="Navas Martin, S" uniqKey="Navas Martin S">S Navas-Martin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author><author><name sortKey="Donaldson, Ef" uniqKey="Donaldson E">EF Donaldson</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, Jf" uniqKey="Chan J">JF Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gralinski, Le" uniqKey="Gralinski L">LE Gralinski</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brian, Da" uniqKey="Brian D">DA Brian</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dediego, Ml" uniqKey="Dediego M">ML DeDiego</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kanzawa, N" uniqKey="Kanzawa N">N Kanzawa</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Tong, Tr" uniqKey="Tong T">TR Tong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tong, Tr" uniqKey="Tong T">TR Tong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Yz" uniqKey="Lee Y">YZ Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Cw" uniqKey="Yang C">CW Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eleouet, Jf" uniqKey="Eleouet J">JF Eleouet</name></author><author><name sortKey="Chilmonczyk, S" uniqKey="Chilmonczyk S">S Chilmonczyk</name></author><author><name sortKey="Besnardeau, L" uniqKey="Besnardeau L">L Besnardeau</name></author><author><name sortKey="Laude, H" uniqKey="Laude H">H Laude</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcbride, R" uniqKey="Mcbride R">R McBride</name></author><author><name sortKey="Van Zyl, M" uniqKey="Van Zyl M">M van Zyl</name></author><author><name sortKey="Fielding, Bc" uniqKey="Fielding B">BC Fielding</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Cw" uniqKey="Yang C">CW Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qiu, Yq" uniqKey="Qiu Y">YQ Qiu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hiscott, J" uniqKey="Hiscott J">J Hiscott</name></author><author><name sortKey="Kwon, H" uniqKey="Kwon H">H Kwon</name></author><author><name sortKey="Genin, P" uniqKey="Genin P">P Genin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jao, Cy" uniqKey="Jao C">CY Jao</name></author><author><name sortKey="Salic, A" uniqKey="Salic A">A Salic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Solomon, S" uniqKey="Solomon S">S Solomon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hui, Ds" uniqKey="Hui D">DS Hui</name></author><author><name sortKey="Memish, Za" uniqKey="Memish Z">ZA Memish</name></author><author><name sortKey="Zumla, A" uniqKey="Zumla A">A Zumla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stohlman, Sa" uniqKey="Stohlman S">SA Stohlman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Ivanyi Nagy, R" uniqKey="Ivanyi Nagy R">R Ivanyi-Nagy</name></author><author><name sortKey="Davidovic, L" uniqKey="Davidovic L">L Davidovic</name></author><author><name sortKey="Khandjian, Ew" uniqKey="Khandjian E">EW Khandjian</name></author><author><name sortKey="Darlix, Jl" uniqKey="Darlix J">JL Darlix</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hiscott, J" uniqKey="Hiscott J">J Hiscott</name></author><author><name sortKey="Nguyen, Tl" uniqKey="Nguyen T">TL Nguyen</name></author><author><name sortKey="Arguello, M" uniqKey="Arguello M">M Arguello</name></author><author><name sortKey="Nakhaei, P" uniqKey="Nakhaei P">P Nakhaei</name></author><author><name sortKey="Paz, S" uniqKey="Paz S">S Paz</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Cw" uniqKey="Yang C">CW Yang</name></author></analytic></biblStruct></listBibl></div1></back></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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