Inhibition of Influenza A Virus (H1N1) Fusion by Benzenesulfonamide Derivatives Targeting Viral Hemagglutinin
Identifieur interne : 000C42 ( Main/Exploration ); précédent : 000C41; suivant : 000C43Inhibition of Influenza A Virus (H1N1) Fusion by Benzenesulfonamide Derivatives Targeting Viral Hemagglutinin
Auteurs : Lei Zhu [République populaire de Chine] ; Yuhuan Li [République populaire de Chine] ; Shaohua Li [République populaire de Chine] ; Haodong Li [République populaire de Chine] ; Zongxing Qiu [République populaire de Chine] ; Chichang Lee [République populaire de Chine] ; Henry Lu [République populaire de Chine] ; Xianfeng Lin [République populaire de Chine] ; Rong Zhao [République populaire de Chine] ; Li Chen [République populaire de Chine] ; Jim Z. Wu [République populaire de Chine] ; Guozhi Tang [République populaire de Chine] ; Wengang Yang [République populaire de Chine]Source :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
Hemagglutinin (HA) of the influenza virus plays a crucial role in the early stage of the viral life cycle by binding to sialic acid on the surface of host epithelial cells and mediating fusion between virus envelope and endosome membrane for the release of viral genomes into the cytoplasm. To initiate virus fusion, endosome pH is lowered by acidification causing an irreversible conformational change of HA, which in turn results in a fusogenic HA. In this study, we describe characterization of an HA inhibitor of influenza H1N1 viruses, RO5464466. One-cycle time course study in MDCK cells showed that this compound acted at an early step of influenza virus replication.
Url:
DOI: 10.1371/journal.pone.0029120
PubMed: 22195002
PubMed Central: 3240648
Affiliations:
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Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Li, Yuhuan" sort="Li, Yuhuan" uniqKey="Li Y" first="Yuhuan" last="Li">Yuhuan Li</name><affiliation wicri:level="3"><nlm:aff id="aff3"><addr-line>Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Li, Shaohua" sort="Li, Shaohua" uniqKey="Li S" first="Shaohua" last="Li">Shaohua Li</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>WuXi AppTec Co., Ltd., Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec Co., Ltd., Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Li, Haodong" sort="Li, Haodong" uniqKey="Li H" first="Haodong" last="Li">Haodong Li</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>WuXi AppTec Co., Ltd., Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec Co., Ltd., Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Qiu, Zongxing" sort="Qiu, Zongxing" uniqKey="Qiu Z" first="Zongxing" last="Qiu">Zongxing Qiu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Chichang" sort="Lee, Chichang" uniqKey="Lee C" first="Chichang" last="Lee">Chichang Lee</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>WuXi AppTec Co., Ltd., Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec Co., Ltd., Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lu, Henry" sort="Lu, Henry" uniqKey="Lu H" first="Henry" last="Lu">Henry Lu</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>WuXi AppTec Co., Ltd., Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>WuXi AppTec Co., Ltd., Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Lin, Xianfeng" sort="Lin, Xianfeng" uniqKey="Lin X" first="Xianfeng" last="Lin">Xianfeng Lin</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Zhao, Rong" sort="Zhao, Rong" uniqKey="Zhao R" first="Rong" last="Zhao">Rong Zhao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Li" sort="Chen, Li" uniqKey="Chen L" first="Li" last="Chen">Li Chen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Jim Z" sort="Wu, Jim Z" uniqKey="Wu J" first="Jim Z." last="Wu">Jim Z. Wu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Tang, Guozhi" sort="Tang, Guozhi" uniqKey="Tang G" first="Guozhi" last="Tang">Guozhi Tang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Wengang" sort="Yang, Wengang" uniqKey="Yang W" first="Wengang" last="Yang">Wengang Yang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Roche Pharma Research and Early Development, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Roche Pharma Research and Early Development, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Hemagglutinin (HA) of the influenza virus plays a crucial role in the early stage of the viral life cycle by binding to sialic acid on the surface of host epithelial cells and mediating fusion between virus envelope and endosome membrane for the release of viral genomes into the cytoplasm. To initiate virus fusion, endosome pH is lowered by acidification causing an irreversible conformational change of HA, which in turn results in a fusogenic HA. In this study, we describe characterization of an HA inhibitor of influenza H1N1 viruses, RO5464466. One-cycle time course study in MDCK cells showed that this compound acted at an early step of influenza virus replication. <xref ref-type="sec" rid="s3">Results</xref> from HA-mediated hemolysis of chicken red blood cells and trypsin sensitivity assay of isolated HA clearly showed that RO5464466 targeted HA. In cell-based assays involving multiple rounds of virus infection and replication, RO5464466 inhibited an established influenza infection. The overall production of progeny viruses, as a result of the compound's inhibitory effect on fusion, was dramatically reduced by 8 log units when compared with a negative control. Furthermore, RO5487624, a close analogue of RO5464466, with pharmacokinetic properties suitable for <italic>in vivo</italic> efficacy studies displayed a protective effect on mice that were lethally challenged with influenza H1N1 virus. These results might benefit further characterization and development of novel anti-influenza agents by targeting viral hemagglutinin.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Wright, Pf" uniqKey="Wright P">PF Wright</name></author><author><name sortKey="Webster, Rg" uniqKey="Webster R">RG Webster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Np" uniqKey="Johnson N">NP Johnson</name></author><author><name sortKey="Mueller, J" uniqKey="Mueller J">J Mueller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lindstrom, Se" uniqKey="Lindstrom S">SE Lindstrom</name></author><author><name sortKey="Cox, Nj" uniqKey="Cox N">NJ Cox</name></author><author><name sortKey="Klimov, A" uniqKey="Klimov A">A Klimov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scholtissek, C" uniqKey="Scholtissek C">C 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D">D Aird</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Zhu, Lei" sort="Zhu, Lei" uniqKey="Zhu L" first="Lei" last="Zhu">Lei Zhu</name></noRegion><name sortKey="Chen, Li" sort="Chen, Li" uniqKey="Chen L" first="Li" last="Chen">Li Chen</name><name sortKey="Lee, Chichang" sort="Lee, Chichang" uniqKey="Lee C" first="Chichang" last="Lee">Chichang Lee</name><name sortKey="Li, Haodong" sort="Li, Haodong" uniqKey="Li H" first="Haodong" last="Li">Haodong Li</name><name sortKey="Li, Shaohua" sort="Li, Shaohua" uniqKey="Li S" first="Shaohua" last="Li">Shaohua Li</name><name sortKey="Li, Yuhuan" sort="Li, Yuhuan" uniqKey="Li Y" first="Yuhuan" last="Li">Yuhuan Li</name><name sortKey="Lin, Xianfeng" sort="Lin, Xianfeng" uniqKey="Lin X" first="Xianfeng" last="Lin">Xianfeng Lin</name><name sortKey="Lu, Henry" sort="Lu, Henry" uniqKey="Lu H" first="Henry" last="Lu">Henry Lu</name><name sortKey="Qiu, Zongxing" sort="Qiu, Zongxing" uniqKey="Qiu Z" first="Zongxing" last="Qiu">Zongxing Qiu</name><name sortKey="Tang, Guozhi" sort="Tang, Guozhi" uniqKey="Tang G" first="Guozhi" last="Tang">Guozhi Tang</name><name sortKey="Wu, Jim Z" sort="Wu, Jim Z" uniqKey="Wu J" first="Jim Z." last="Wu">Jim Z. Wu</name><name sortKey="Yang, Wengang" sort="Yang, Wengang" uniqKey="Yang W" first="Wengang" last="Yang">Wengang Yang</name><name sortKey="Zhao, Rong" sort="Zhao, Rong" uniqKey="Zhao R" first="Rong" last="Zhao">Rong Zhao</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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