Novel influenza virus NS1 antagonists block replication and restore innate immune function.
Identifieur interne : 002A65 ( Main/Exploration ); précédent : 002A64; suivant : 002A66Novel influenza virus NS1 antagonists block replication and restore innate immune function.
Auteurs : Dipanwita Basu [États-Unis] ; Marcin P. Walkiewicz ; Matthew Frieman ; Ralph S. Baric ; David T. Auble ; Daniel A. EngelSource :
- Journal of virology [ 1098-5514 ] ; 2009.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (pharmacologie), Humains, Interféron bêta (biosynthèse), Lignée cellulaire, Protéines virales non structurales (antagonistes et inhibiteurs), Réplication virale (), Virus de la grippe A (), Virus de la grippe A (immunologie), Virus de la grippe A (physiologie), Virus du SRAS (), Virus respiratoires syncytiaux ().
- MESH :
- antagonistes et inhibiteurs : Protéines virales non structurales.
- biosynthèse : Interféron bêta.
- immunologie : Virus de la grippe A.
- pharmacologie : Antiviraux.
- physiologie : Virus de la grippe A.
- Animaux, Humains, Lignée cellulaire, Réplication virale, Virus de la grippe A, Virus du SRAS, Virus respiratoires syncytiaux.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Cell Line, Humans, Influenza A virus (drug effects), Influenza A virus (immunology), Influenza A virus (physiology), Interferon-beta (biosynthesis), Respiratory Syncytial Viruses (drug effects), SARS Virus (drug effects), Viral Nonstructural Proteins (antagonists & inhibitors), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Viral Nonstructural Proteins.
- chemical , biosynthesis : Interferon-beta.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Influenza A virus, Respiratory Syncytial Viruses, SARS Virus, Virus Replication.
- immunology : Influenza A virus.
- physiology : Influenza A virus.
- Animals, Cell Line, Humans.
Abstract
The innate immune system guards against virus infection through a variety of mechanisms including mobilization of the host interferon system, which attacks viral products mainly at a posttranscriptional level. The influenza virus NS1 protein is a multifunctional facilitator of virus replication, one of whose actions is to antagonize the interferon response. Since NS1 is required for efficient virus replication, it was reasoned that chemical inhibitors of this protein could be used to further understand virus-host interactions and also serve as potential new antiviral agents. A yeast-based assay was developed to identify compounds that phenotypically suppress NS1 function. Several such compounds exhibited significant activity specifically against influenza A virus in cell culture but had no effect on the replication of another RNA virus, respiratory syncytial virus. Interestingly, cells lacking an interferon response were drug resistant, suggesting that the compounds block interactions between NS1 and the interferon system. Accordingly, the compounds reversed the inhibition of beta interferon mRNA induction during infection, which is known to be caused by NS1. In addition, the compounds blocked the ability of NS1 protein to inhibit double-stranded RNA-dependent activation of a transfected beta interferon promoter construct. The effects of the compounds were specific to NS1, because they had no effect on the ability of the severe acute respiratory syndrome coronavirus papainlike protease protein to block beta interferon promoter activation. These data demonstrate that the function of NS1 can be modulated by chemical inhibitors and that such inhibitors will be useful as probes of biological function and as starting points for clinical drug development.
DOI: 10.1128/JVI.01805-08
PubMed: 19052087
Affiliations:
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Le document en format XML
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Walkiewicz</name></author><author><name sortKey="Frieman, Matthew" sort="Frieman, Matthew" uniqKey="Frieman M" first="Matthew" last="Frieman">Matthew Frieman</name></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name></author><author><name sortKey="Auble, David T" sort="Auble, David T" uniqKey="Auble D" first="David T" last="Auble">David T. Auble</name></author><author><name sortKey="Engel, Daniel A" sort="Engel, Daniel A" uniqKey="Engel D" first="Daniel A" last="Engel">Daniel A. Engel</name></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Cell Line</term><term>Humans</term><term>Influenza A virus (drug effects)</term><term>Influenza A virus (immunology)</term><term>Influenza A virus (physiology)</term><term>Interferon-beta (biosynthesis)</term><term>Respiratory Syncytial Viruses (drug effects)</term><term>SARS Virus (drug effects)</term><term>Viral Nonstructural Proteins (antagonists & inhibitors)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Humains</term><term>Interféron bêta (biosynthèse)</term><term>Lignée cellulaire</term><term>Protéines virales non structurales (antagonistes et inhibiteurs)</term><term>Réplication virale ()</term><term>Virus de la grippe A ()</term><term>Virus de la grippe A (immunologie)</term><term>Virus de la grippe A (physiologie)</term><term>Virus du SRAS ()</term><term>Virus respiratoires syncytiaux ()</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Interferon-beta</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales non structurales</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Interféron bêta</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Influenza A virus</term><term>Respiratory Syncytial Viruses</term><term>SARS Virus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Humans</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Lignée cellulaire</term><term>Réplication virale</term><term>Virus de la grippe A</term><term>Virus du SRAS</term><term>Virus respiratoires syncytiaux</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The innate immune system guards against virus infection through a variety of mechanisms including mobilization of the host interferon system, which attacks viral products mainly at a posttranscriptional level. The influenza virus NS1 protein is a multifunctional facilitator of virus replication, one of whose actions is to antagonize the interferon response. Since NS1 is required for efficient virus replication, it was reasoned that chemical inhibitors of this protein could be used to further understand virus-host interactions and also serve as potential new antiviral agents. A yeast-based assay was developed to identify compounds that phenotypically suppress NS1 function. Several such compounds exhibited significant activity specifically against influenza A virus in cell culture but had no effect on the replication of another RNA virus, respiratory syncytial virus. Interestingly, cells lacking an interferon response were drug resistant, suggesting that the compounds block interactions between NS1 and the interferon system. Accordingly, the compounds reversed the inhibition of beta interferon mRNA induction during infection, which is known to be caused by NS1. In addition, the compounds blocked the ability of NS1 protein to inhibit double-stranded RNA-dependent activation of a transfected beta interferon promoter construct. The effects of the compounds were specific to NS1, because they had no effect on the ability of the severe acute respiratory syndrome coronavirus papainlike protease protein to block beta interferon promoter activation. These data demonstrate that the function of NS1 can be modulated by chemical inhibitors and that such inhibitors will be useful as probes of biological function and as starting points for clinical drug development.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Auble, David T" sort="Auble, David T" uniqKey="Auble D" first="David T" last="Auble">David T. Auble</name><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name><name sortKey="Engel, Daniel A" sort="Engel, Daniel A" uniqKey="Engel D" first="Daniel A" last="Engel">Daniel A. Engel</name><name sortKey="Frieman, Matthew" sort="Frieman, Matthew" uniqKey="Frieman M" first="Matthew" last="Frieman">Matthew Frieman</name><name sortKey="Walkiewicz, Marcin P" sort="Walkiewicz, Marcin P" uniqKey="Walkiewicz M" first="Marcin P" last="Walkiewicz">Marcin P. Walkiewicz</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Basu, Dipanwita" sort="Basu, Dipanwita" uniqKey="Basu D" first="Dipanwita" last="Basu">Dipanwita Basu</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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