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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides</title><author><name sortKey="Chukkapalli, Vineela" sort="Chukkapalli, Vineela" uniqKey="Chukkapalli V" first="Vineela" last="Chukkapalli">Vineela Chukkapalli</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author><author><name sortKey="Berger, Kristi L" sort="Berger, Kristi L" uniqKey="Berger K" first="Kristi L." last="Berger">Kristi L. Berger</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author><author><name sortKey="Kelly, Sean M" sort="Kelly, Sean M" uniqKey="Kelly S" first="Sean M." last="Kelly">Sean M. Kelly</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author><author><name sortKey="Thomas, Meryl" sort="Thomas, Meryl" uniqKey="Thomas M" first="Meryl" last="Thomas">Meryl Thomas</name><affiliation><nlm:aff id="A2">Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260</nlm:aff></affiliation></author><author><name sortKey="Deiters, Alexander" sort="Deiters, Alexander" uniqKey="Deiters A" first="Alexander" last="Deiters">Alexander Deiters</name><affiliation><nlm:aff id="A2">Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260</nlm:aff></affiliation></author><author><name sortKey="Randall, Glenn" sort="Randall, Glenn" uniqKey="Randall G" first="Glenn" last="Randall">Glenn Randall</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25546252</idno><idno type="pmc">4323755</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323755</idno><idno type="RBID">PMC:4323755</idno><idno type="doi">10.1016/j.virol.2014.12.018</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000D08</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D08</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides</title><author><name sortKey="Chukkapalli, Vineela" sort="Chukkapalli, Vineela" uniqKey="Chukkapalli V" first="Vineela" last="Chukkapalli">Vineela Chukkapalli</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author><author><name sortKey="Berger, Kristi L" sort="Berger, Kristi L" uniqKey="Berger K" first="Kristi L." last="Berger">Kristi L. Berger</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author><author><name sortKey="Kelly, Sean M" sort="Kelly, Sean M" uniqKey="Kelly S" first="Sean M." last="Kelly">Sean M. Kelly</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author><author><name sortKey="Thomas, Meryl" sort="Thomas, Meryl" uniqKey="Thomas M" first="Meryl" last="Thomas">Meryl Thomas</name><affiliation><nlm:aff id="A2">Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260</nlm:aff></affiliation></author><author><name sortKey="Deiters, Alexander" sort="Deiters, Alexander" uniqKey="Deiters A" first="Alexander" last="Deiters">Alexander Deiters</name><affiliation><nlm:aff id="A2">Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260</nlm:aff></affiliation></author><author><name sortKey="Randall, Glenn" sort="Randall, Glenn" uniqKey="Randall G" first="Glenn" last="Randall">Glenn Randall</name><affiliation><nlm:aff id="A1">Department of Microbiology, The University of Chicago, Chicago IL 60637</nlm:aff></affiliation></author></analytic><series><title level="j">Virology</title><idno type="ISSN">0042-6822</idno><idno type="eISSN">1096-0341</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Combinations of direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) have the potential to revolutionize the HCV therapeutic regime. An integral component of DAA combination therapies are HCV NS5A inhibitors. It has previously been proposed that NS5A DAAs inhibit two functions of NS5A: RNA replication and virion assembly. In this study, we characterize the impact of a prototype NS5A DAA, daclatasvir (DCV), on HCV replication compartment formation. DCV impaired HCV replicase localization and NS5A motility. In order to characterize the mechanism behind altered HCV replicase localization, we examined the impact of DCV on the interaction of NS5A with its essential cellular cofactor, phosphatidylinositol-4-kinase III α (PI4KA). We observed that DCV does not inhibit PI4KA directly, nor does it impair early events of the NS5A-PI4KA interaction that can occur when NS5A is expressed alone. NS5A functions that are unaffected by DCV include PI4KA binding, as determined by co-immunoprecipitation, and a basal accumulation of the PI4KA product, PI4P. However, DCV impairs late steps in PI4KA activation that requires NS5A expressed in the context of the HCV polyprotein. These NS5A functions include hyper-stimulation of PI4P levels and appropriate replication compartment formation. The data are most consistent with a model wherein DCV inhibits conformational changes in the NS5A protein or protein complex formations that occur in the context of HCV polyprotein expression and stimulate PI4P hyper-accumulation and replication compartment formation.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">0110674</journal-id><journal-id journal-id-type="pubmed-jr-id">8015</journal-id><journal-id journal-id-type="nlm-ta">Virology</journal-id><journal-id journal-id-type="iso-abbrev">Virology</journal-id><journal-title-group><journal-title>Virology</journal-title></journal-title-group><issn pub-type="ppub">0042-6822</issn><issn pub-type="epub">1096-0341</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25546252</article-id><article-id pub-id-type="pmc">4323755</article-id><article-id pub-id-type="doi">10.1016/j.virol.2014.12.018</article-id><article-id pub-id-type="manuscript">NIHMS650764</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Daclatasvir inhibits hepatitis C virus NS5A motility and hyper-accumulation of phosphoinositides</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chukkapalli</surname><given-names>Vineela</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Berger</surname><given-names>Kristi L.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="author-notes" rid="FN1">3</xref></contrib><contrib contrib-type="author"><name><surname>Kelly</surname><given-names>Sean M.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Meryl</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Deiters</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Randall</surname><given-names>Glenn</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="cor1">#</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Microbiology, The University of Chicago, Chicago IL 60637</aff><aff id="A2"><label>2</label>Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260</aff><author-notes><corresp id="cor1"><label>#</label><bold>Corresponding Author:</bold> Glenn Randall PhD, Associate Professor, Department of Microbiology, The University of Chicago, CLSC 707B, 920 East 58th Street, Chicago, Illinois 60637, Phone: 773-702-5673, Fax: 773-834-8150, (<email>grandall@bsd.uchicago.edu</email>)</corresp><fn id="FN1" fn-type="present-address"><label>3</label><p id="P1"><bold>Present Address:</bold> Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>20</day><month>12</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>26</day><month>12</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>2</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>2</month><year>2016</year></pub-date><volume>476</volume><fpage>168</fpage><lpage>179</lpage><pmc-comment>elocation-id from pubmed: 10.1016/j.virol.2014.12.018</pmc-comment>
<permissions><copyright-statement>© 2014 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2014</copyright-year></permissions><abstract><p id="P2">Combinations of direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) have the potential to revolutionize the HCV therapeutic regime. An integral component of DAA combination therapies are HCV NS5A inhibitors. It has previously been proposed that NS5A DAAs inhibit two functions of NS5A: RNA replication and virion assembly. In this study, we characterize the impact of a prototype NS5A DAA, daclatasvir (DCV), on HCV replication compartment formation. DCV impaired HCV replicase localization and NS5A motility. In order to characterize the mechanism behind altered HCV replicase localization, we examined the impact of DCV on the interaction of NS5A with its essential cellular cofactor, phosphatidylinositol-4-kinase III α (PI4KA). We observed that DCV does not inhibit PI4KA directly, nor does it impair early events of the NS5A-PI4KA interaction that can occur when NS5A is expressed alone. NS5A functions that are unaffected by DCV include PI4KA binding, as determined by co-immunoprecipitation, and a basal accumulation of the PI4KA product, PI4P. However, DCV impairs late steps in PI4KA activation that requires NS5A expressed in the context of the HCV polyprotein. These NS5A functions include hyper-stimulation of PI4P levels and appropriate replication compartment formation. The data are most consistent with a model wherein DCV inhibits conformational changes in the NS5A protein or protein complex formations that occur in the context of HCV polyprotein expression and stimulate PI4P hyper-accumulation and replication compartment formation.</p></abstract><kwd-group><kwd>Phosphatidylinositol-4-kinase alpha</kwd><kwd>Phosphatidylinositol-4-phosphate</kwd><kwd>HCV replication complex</kwd><kwd>direct-acting anti-virals</kwd></kwd-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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