Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition
Identifieur interne : 000C06 ( Pmc/Curation ); précédent : 000C05; suivant : 000C07Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition
Auteurs : Christopher J. Vavricka [République populaire de Chine] ; Qing Li [République populaire de Chine] ; Yan Wu [République populaire de Chine] ; Jianxun Qi [République populaire de Chine] ; Mingyang Wang [République populaire de Chine] ; Yue Liu [République populaire de Chine] ; Feng Gao [République populaire de Chine] ; Jun Liu [République populaire de Chine] ; Enguang Feng [République populaire de Chine] ; Jianhua He [République populaire de Chine] ; Jinfang Wang [République populaire de Chine] ; Hong Liu [République populaire de Chine] ; Hualiang Jiang [République populaire de Chine] ; George F. Gao [République populaire de Chine]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2011.
Abstract
The 2009 H1N1 influenza pandemic (pH1N1) led to record sales of neuraminidase (NA) inhibitors, which has contributed significantly to the recent increase in oseltamivir-resistant viruses. Therefore, development and careful evaluation of novel NA inhibitors is of great interest. Recently, a highly potent NA inhibitor, laninamivir, has been approved for use in Japan. Laninamivir is effective using a single inhaled dose via its octanoate prodrug (CS-8958) and has been demonstrated to be effective against oseltamivir-resistant NA
Url:
DOI: 10.1371/journal.ppat.1002249
PubMed: 22028647
PubMed Central: 3197600
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Vavricka</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Li, Qing" sort="Li, Qing" uniqKey="Li Q" first="Qing" last="Li">Qing Li</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>School of Life Sciences, University of Science and Technology of China, Hefei, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Life Sciences, University of Science and Technology of China, Hefei</wicri:regionArea></affiliation></author><author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Qi, Jianxun" 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Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Jinfang" sort="Wang, Jinfang" uniqKey="Wang J" first="Jinfang" last="Wang">Jinfang Wang</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Hong" sort="Liu, Hong" uniqKey="Liu H" first="Hong" 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Vavricka</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Li, Qing" sort="Li, Qing" uniqKey="Li Q" first="Qing" last="Li">Qing Li</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>School of Life Sciences, University of Science and Technology of China, Hefei, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Life Sciences, University of Science and Technology of China, Hefei</wicri:regionArea></affiliation></author><author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Qi, Jianxun" sort="Qi, Jianxun" uniqKey="Qi J" first="Jianxun" last="Qi">Jianxun Qi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Mingyang" sort="Wang, Mingyang" uniqKey="Wang M" first="Mingyang" last="Wang">Mingyang Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Graduate University, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Graduate University, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Yue" sort="Liu, Yue" uniqKey="Liu Y" first="Yue" last="Liu">Yue Liu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Feng" sort="Gao, Feng" uniqKey="Gao F" first="Feng" last="Gao">Feng Gao</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Jun" sort="Liu, Jun" uniqKey="Liu J" first="Jun" last="Liu">Jun Liu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Feng, Enguang" sort="Feng, Enguang" uniqKey="Feng E" first="Enguang" last="Feng">Enguang Feng</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="He, Jianhua" sort="He, Jianhua" uniqKey="He J" first="Jianhua" last="He">Jianhua He</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Jinfang" sort="Wang, Jinfang" uniqKey="Wang J" first="Jinfang" last="Wang">Jinfang Wang</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Hong" sort="Liu, Hong" uniqKey="Liu H" first="Hong" last="Liu">Hong Liu</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Hualiang" sort="Jiang, Hualiang" uniqKey="Jiang H" first="Hualiang" last="Jiang">Hualiang Jiang</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai</wicri:regionArea></affiliation></author><author><name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>School of Life Sciences, University of Science and Technology of China, Hefei, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Life Sciences, University of Science and Technology of China, Hefei</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Graduate University, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Graduate University, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</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>The 2009 H1N1 influenza pandemic (pH1N1) led to record sales of neuraminidase (NA) inhibitors, which has contributed significantly to the recent increase in oseltamivir-resistant viruses. Therefore, development and careful evaluation of novel NA inhibitors is of great interest. Recently, a highly potent NA inhibitor, laninamivir, has been approved for use in Japan. Laninamivir is effective using a single inhaled dose via its octanoate prodrug (CS-8958) and has been demonstrated to be effective against oseltamivir-resistant NA <italic>in vitro</italic>. However, effectiveness of laninamivir octanoate prodrug against oseltamivir-resistant influenza infection in adults has not been demonstrated. NA is classified into 2 groups based upon phylogenetic analysis and it is becoming clear that each group has some distinct structural features. Recently, we found that pH1N1 N1 NA (p09N1) is an atypical group 1 NA with some group 2-like features in its active site (lack of a 150-cavity). Furthermore, it has been reported that certain oseltamivir-resistant substitutions in the NA active site are group 1 specific. In order to comprehensively evaluate the effectiveness of laninamivir, we utilized recombinant N5 (typical group 1), p09N1 (atypical group 1) and N2 from the 1957 pandemic H2N2 (p57N2) (typical group 2) to carry out <italic>in vitro</italic> inhibition assays. We found that laninamivir and its octanoate prodrug display group specific preferences to different influenza NAs and provide the structural basis of their specific action based upon their novel complex crystal structures. Our results indicate that laninamivir and zanamivir are more effective against group 1 NA with a 150-cavity than group 2 NA with no 150-cavity. Furthermore, we have found that the laninamivir octanoate prodrug has a unique binding mode in p09N1 that is different from that of group 2 p57N2, but with some similarities to NA-oseltamivir binding, which provides additional insight into group specific differences of oseltamivir binding and resistance.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Dawood, Fs" uniqKey="Dawood F">FS Dawood</name></author><author><name sortKey="Jain, S" uniqKey="Jain S">S Jain</name></author><author><name sortKey="Finelli, L" uniqKey="Finelli L">L Finelli</name></author><author><name sortKey="Shaw, Mw" uniqKey="Shaw M">MW Shaw</name></author><author><name sortKey="Lindstrom, S" uniqKey="Lindstrom S">S Lindstrom</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Tt" uniqKey="Wang T">TT Wang</name></author><author><name sortKey="Palese, P" uniqKey="Palese P">P 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sortKey="Moss, Ds" uniqKey="Moss D">DS Moss</name></author><author><name sortKey="Thornton, Jm" uniqKey="Thornton J">JM Thornton</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ramachandran, Gn" uniqKey="Ramachandran G">GN Ramachandran</name></author><author><name sortKey="Ramakrishnan, C" uniqKey="Ramakrishnan C">C Ramakrishnan</name></author><author><name sortKey="Sasisekharan, V" uniqKey="Sasisekharan V">V Sasisekharan</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plospath</journal-id><journal-title-group><journal-title>PLoS Pathogens</journal-title></journal-title-group><issn pub-type="ppub">1553-7366</issn><issn pub-type="epub">1553-7374</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22028647</article-id><article-id pub-id-type="pmc">3197600</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-11-00921</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1002249</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Protein Structure</subject></subj-group></subj-group><subj-group><subject>Drug Discovery</subject><subject>Glycobiology</subject></subj-group></subj-group><subj-group><subject>Proteomics</subject></subj-group></subj-group></article-categories><title-group><article-title>Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition</article-title><alt-title alt-title-type="running-head">Laninamivir-NA Group Specific Mechanisms</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Vavricka</surname><given-names>Christopher J.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Li</surname><given-names>Qing</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Wu</surname><given-names>Yan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Qi</surname><given-names>Jianxun</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Mingyang</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Yue</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Feng</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jun</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Feng</surname><given-names>Enguang</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>He</surname><given-names>Jianhua</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Jinfang</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Hong</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Hualiang</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>George F.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</addr-line></aff><aff id="aff2"><label>2</label><addr-line>School of Life Sciences, University of Science and Technology of China, Hefei, China</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Graduate University, Chinese Academy of Sciences, Beijing, China</addr-line></aff><aff id="aff4"><label>4</label><addr-line>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China</addr-line></aff><aff id="aff5"><label>5</label><addr-line>State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Pekosz</surname><given-names>Andrew</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">Johns Hopkins University - Bloomberg School of Public Health, United States of America</aff><author-notes><corresp id="cor1">* E-mail: <email>gaof@im.ac.cn</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: CJV QL JQ GFG. Performed the experiments: CJV QL YW JQ MW YL. Analyzed the data: CJV QL YW YL JQ FG JL GFG. Contributed reagents/materials/analysis tools: EF JH JW HL HJ. Wrote the paper: CJV GFG.</p></fn></author-notes><pub-date pub-type="collection"><month>10</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>20</day><month>10</month><year>2011</year></pub-date><volume>7</volume><issue>10</issue><elocation-id>e1002249</elocation-id><history><date date-type="received"><day>28</day><month>4</month><year>2011</year></date><date date-type="accepted"><day>20</day><month>7</month><year>2011</year></date></history><permissions><copyright-statement>Vavricka et al.</copyright-statement><copyright-year>2011</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><p>The 2009 H1N1 influenza pandemic (pH1N1) led to record sales of neuraminidase (NA) inhibitors, which has contributed significantly to the recent increase in oseltamivir-resistant viruses. Therefore, development and careful evaluation of novel NA inhibitors is of great interest. Recently, a highly potent NA inhibitor, laninamivir, has been approved for use in Japan. Laninamivir is effective using a single inhaled dose via its octanoate prodrug (CS-8958) and has been demonstrated to be effective against oseltamivir-resistant NA <italic>in vitro</italic>. However, effectiveness of laninamivir octanoate prodrug against oseltamivir-resistant influenza infection in adults has not been demonstrated. NA is classified into 2 groups based upon phylogenetic analysis and it is becoming clear that each group has some distinct structural features. Recently, we found that pH1N1 N1 NA (p09N1) is an atypical group 1 NA with some group 2-like features in its active site (lack of a 150-cavity). Furthermore, it has been reported that certain oseltamivir-resistant substitutions in the NA active site are group 1 specific. In order to comprehensively evaluate the effectiveness of laninamivir, we utilized recombinant N5 (typical group 1), p09N1 (atypical group 1) and N2 from the 1957 pandemic H2N2 (p57N2) (typical group 2) to carry out <italic>in vitro</italic> inhibition assays. We found that laninamivir and its octanoate prodrug display group specific preferences to different influenza NAs and provide the structural basis of their specific action based upon their novel complex crystal structures. Our results indicate that laninamivir and zanamivir are more effective against group 1 NA with a 150-cavity than group 2 NA with no 150-cavity. Furthermore, we have found that the laninamivir octanoate prodrug has a unique binding mode in p09N1 that is different from that of group 2 p57N2, but with some similarities to NA-oseltamivir binding, which provides additional insight into group specific differences of oseltamivir binding and resistance.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>The influenza neuraminidase (NA) enzyme is the most successful drug target against the seasonal and pandemic flu. The 2009 H1N1 flu pandemic led to record sales of the NA inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza). Recently, a new drug, laninamivir (Inavir), has been approved for use in Japan can also be administered effectively using a single dose via its octanoate prodrug (CS-8958), however its effectiveness against oseltamivir-resistant influenza infection has not been demonstrated in clinical studies. In this study we comprehensively evaluate the effectiveness of laninamivir and its prodrug using NA from different groups with different active site features. We expressed and purified a group 2 NA from the 1957 pandemic H2N2, an atypical group 1 NA from the 2009 H1N1 pandemic and a group 1 NA from avian H12N5. NA inhibition was assayed and NAs were further crystallized with each inhibitor to determine the structural basis of their action. We found that laninamivir inhibition is highly potent for each NA, however binding and inhibition of laninamivir and its prodrug showed group specific preferences. Our results provide the structural and functional basis of NA inhibition using classical and novel inhibitors, with NAs from multiple serotypes with different properties.</p></abstract><counts><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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