Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor
Identifieur interne : 000D07 ( Ncbi/Checkpoint ); précédent : 000D06; suivant : 000D08Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor
Auteurs : Yan Wu [République populaire de Chine] ; Feng Gao [République populaire de Chine] ; Jianxun Qi [République populaire de Chine] ; Yuhai Bi [République populaire de Chine] ; Lifeng Fu [République populaire de Chine] ; Sankar Mohan [Canada] ; Yuhang Chen [République populaire de Chine] ; Xuebing Li [République populaire de Chine] ; B. Mario Pinto [Canada] ; Christopher J. Vavricka [République populaire de Chine] ; Po Tien [République populaire de Chine] ; George F. Gao [République populaire de Chine]Source :
- Journal of Virology [ 0022-538X ] ; 2016.
Abstract
Influenza virus neuraminidase (NA) drug resistance is one of the challenges to preparedness against epidemic and pandemic influenza virus infections. NA N1- and N2-containing influenza viruses are the primary cause of seasonal epidemics and past pandemics. The structural and functional basis underlying drug resistance of the influenza virus N1 NA is well characterized. Yet drug resistance of the N2 strain is not well understood. Here, we confirm that replacement of N2 E119 or I222 results in multidrug resistance, and when the replacements occur together, the sensitivity to NA inhibitors (NAI) is reduced severely. Using crystallographic studies, we showed that E119 replacement results in a loss of hydrogen bonding to oseltamivir and zanamivir, whereas I222 replacement results in a change in the hydrophobic environment that is critical for oseltamivir binding. Moreover, we found that MS-257, a zanamivir-oseltamivir hybrid inhibitor, is less susceptible to drug resistance. The binding mode of MS-257 shows that increased hydrogen bonding interactions between the inhibitor and NA active site anchor the inhibitor within the active site and allow adjustments in response to active-site modifications. Such stability is likely responsible for the observed reduced susceptibility to drug resistance. MS-257 serves as a next-generation anti-influenza virus drug candidate and serves also as a scaffold for further design of NAIs.
Url:
DOI: 10.1128/JVI.01703-16
PubMed: 27654293
PubMed Central: 5110174
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 000695
- to stream Pmc, to step Curation: 000695
- to stream Pmc, to step Checkpoint: 000292
- to stream Ncbi, to step Merge: 000D07
- to stream Ncbi, to step Curation: 000D07
Links to Exploration step
PMC:5110174Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor</title>
<author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff6">Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff7">University of Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>University of Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gao, Feng" sort="Gao, Feng" uniqKey="Gao F" first="Feng" last="Gao">Feng Gao</name>
<affiliation wicri:level="3"><nlm:aff id="aff2">Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Qi, Jianxun" sort="Qi, Jianxun" uniqKey="Qi J" first="Jianxun" last="Qi">Jianxun Qi</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bi, Yuhai" sort="Bi, Yuhai" uniqKey="Bi Y" first="Yuhai" last="Bi">Yuhai Bi</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff6">Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fu, Lifeng" sort="Fu, Lifeng" uniqKey="Fu L" first="Lifeng" last="Fu">Lifeng Fu</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mohan, Sankar" sort="Mohan, Sankar" uniqKey="Mohan S" first="Sankar" last="Mohan">Sankar Mohan</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Chemistry, Simon Fraser University, Burnaby, BC</wicri:regionArea>
<wicri:noRegion>BC</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chen, Yuhang" sort="Chen, Yuhang" uniqKey="Chen Y" first="Yuhang" last="Chen">Yuhang Chen</name>
<affiliation wicri:level="3"><nlm:aff id="aff2">Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Li, Xuebing" sort="Li, Xuebing" uniqKey="Li X" first="Xuebing" last="Li">Xuebing Li</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pinto, B Mario" sort="Pinto, B Mario" uniqKey="Pinto B" first="B. Mario" last="Pinto">B. Mario Pinto</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Chemistry, Simon Fraser University, Burnaby, BC</wicri:regionArea>
<wicri:noRegion>BC</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vavricka, Christopher J" sort="Vavricka, Christopher J" uniqKey="Vavricka C" first="Christopher J." last="Vavricka">Christopher J. Vavricka</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tien, Po" sort="Tien, Po" uniqKey="Tien P" first="Po" last="Tien">Po Tien</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</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="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff5">Research Network of Immunity and Health, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Research Network of Immunity and Health, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff6">Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">27654293</idno>
<idno type="pmc">5110174</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110174</idno>
<idno type="RBID">PMC:5110174</idno>
<idno type="doi">10.1128/JVI.01703-16</idno>
<date when="2016">2016</date>
<idno type="wicri:Area/Pmc/Corpus">000695</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000695</idno>
<idno type="wicri:Area/Pmc/Curation">000695</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000695</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000292</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000292</idno>
<idno type="wicri:Area/Ncbi/Merge">000D07</idno>
<idno type="wicri:Area/Ncbi/Curation">000D07</idno>
<idno type="wicri:Area/Ncbi/Checkpoint">000D07</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor</title>
<author><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff6">Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff7">University of Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>University of Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gao, Feng" sort="Gao, Feng" uniqKey="Gao F" first="Feng" last="Gao">Feng Gao</name>
<affiliation wicri:level="3"><nlm:aff id="aff2">Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Qi, Jianxun" sort="Qi, Jianxun" uniqKey="Qi J" first="Jianxun" last="Qi">Jianxun Qi</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Bi, Yuhai" sort="Bi, Yuhai" uniqKey="Bi Y" first="Yuhai" last="Bi">Yuhai Bi</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff6">Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fu, Lifeng" sort="Fu, Lifeng" uniqKey="Fu L" first="Lifeng" last="Fu">Lifeng Fu</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mohan, Sankar" sort="Mohan, Sankar" uniqKey="Mohan S" first="Sankar" last="Mohan">Sankar Mohan</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Chemistry, Simon Fraser University, Burnaby, BC</wicri:regionArea>
<wicri:noRegion>BC</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Chen, Yuhang" sort="Chen, Yuhang" uniqKey="Chen Y" first="Yuhang" last="Chen">Yuhang Chen</name>
<affiliation wicri:level="3"><nlm:aff id="aff2">Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Li, Xuebing" sort="Li, Xuebing" uniqKey="Li X" first="Xuebing" last="Li">Xuebing Li</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pinto, B Mario" sort="Pinto, B Mario" uniqKey="Pinto B" first="B. Mario" last="Pinto">B. Mario Pinto</name>
<affiliation wicri:level="1"><nlm:aff id="aff3">Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Department of Chemistry, Simon Fraser University, Burnaby, BC</wicri:regionArea>
<wicri:noRegion>BC</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vavricka, Christopher J" sort="Vavricka, Christopher J" uniqKey="Vavricka C" first="Christopher J." last="Vavricka">Christopher J. Vavricka</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Tien, Po" sort="Tien, Po" uniqKey="Tien P" first="Po" last="Tien">Po Tien</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</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="3"><nlm:aff id="aff1">CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</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>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff4">National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff5">Research Network of Immunity and Health, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Research Network of Immunity and Health, Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff6">Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Center for Influenza Research and Early-warning, Institute of Microbiology, Chinese Academy of Sciences, Beijing</wicri:regionArea>
<placeName><settlement type="city">Pékin</settlement>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Virology</title>
<idno type="ISSN">0022-538X</idno>
<idno type="eISSN">1098-5514</idno>
<imprint><date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>ABSTRACT</title>
<p>Influenza virus neuraminidase (NA) drug resistance is one of the challenges to preparedness against epidemic and pandemic influenza virus infections. NA N1- and N2-containing influenza viruses are the primary cause of seasonal epidemics and past pandemics. The structural and functional basis underlying drug resistance of the influenza virus N1 NA is well characterized. Yet drug resistance of the N2 strain is not well understood. Here, we confirm that replacement of N2 E119 or I222 results in multidrug resistance, and when the replacements occur together, the sensitivity to NA inhibitors (NAI) is reduced severely. Using crystallographic studies, we showed that E119 replacement results in a loss of hydrogen bonding to oseltamivir and zanamivir, whereas I222 replacement results in a change in the hydrophobic environment that is critical for oseltamivir binding. Moreover, we found that MS-257, a zanamivir-oseltamivir hybrid inhibitor, is less susceptible to drug resistance. The binding mode of MS-257 shows that increased hydrogen bonding interactions between the inhibitor and NA active site anchor the inhibitor within the active site and allow adjustments in response to active-site modifications. Such stability is likely responsible for the observed reduced susceptibility to drug resistance. MS-257 serves as a next-generation anti-influenza virus drug candidate and serves also as a scaffold for further design of NAIs.
</p>
<p><bold>IMPORTANCE</bold>
Oseltamivir and zanamivir are the two major antiviral drugs available for the treatment of influenza virus infections. However, multidrug-resistant viruses have emerged in clinical cases, which pose a challenge for the development of new drugs. N1 and N2 subtypes exist in the viruses which cause seasonal epidemics and past pandemics. Although N1 drug resistance is well characterized, the molecular mechanisms underlying N2 drug resistance are unknown. A previous report showed that an N2 E119V/I222L dual mutant conferred drug resistance to seasonal influenza virus. Here, we confirm that these substitutions result in multidrug resistance and dramatically reduced sensitivity to NAI. We further elucidate the molecular mechanism underlying N2 drug resistance by solving crystal structures of the N2 E119V and I222L mutants and the dual mutant. Most importantly, we found that a novel oseltamivir-zanamivir hybrid inhibitor, MS-257, remains more effective against drug-resistant N2 and is a promising candidate as a next-generation anti-influenza virus drug.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Canada</li>
<li>République populaire de Chine</li>
</country>
<settlement><li>Pékin</li>
</settlement>
</list>
<tree><country name="République populaire de Chine"><noRegion><name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name>
</noRegion>
<name sortKey="Bi, Yuhai" sort="Bi, Yuhai" uniqKey="Bi Y" first="Yuhai" last="Bi">Yuhai Bi</name>
<name sortKey="Bi, Yuhai" sort="Bi, Yuhai" uniqKey="Bi Y" first="Yuhai" last="Bi">Yuhai Bi</name>
<name sortKey="Chen, Yuhang" sort="Chen, Yuhang" uniqKey="Chen Y" first="Yuhang" last="Chen">Yuhang Chen</name>
<name sortKey="Fu, Lifeng" sort="Fu, Lifeng" uniqKey="Fu L" first="Lifeng" last="Fu">Lifeng Fu</name>
<name sortKey="Gao, Feng" sort="Gao, Feng" uniqKey="Gao F" first="Feng" last="Gao">Feng Gao</name>
<name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name>
<name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name>
<name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name>
<name sortKey="Gao, George F" sort="Gao, George F" uniqKey="Gao G" first="George F." last="Gao">George F. Gao</name>
<name sortKey="Li, Xuebing" sort="Li, Xuebing" uniqKey="Li X" first="Xuebing" last="Li">Xuebing Li</name>
<name sortKey="Qi, Jianxun" sort="Qi, Jianxun" uniqKey="Qi J" first="Jianxun" last="Qi">Jianxun Qi</name>
<name sortKey="Tien, Po" sort="Tien, Po" uniqKey="Tien P" first="Po" last="Tien">Po Tien</name>
<name sortKey="Vavricka, Christopher J" sort="Vavricka, Christopher J" uniqKey="Vavricka C" first="Christopher J." last="Vavricka">Christopher J. Vavricka</name>
<name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name>
<name sortKey="Wu, Yan" sort="Wu, Yan" uniqKey="Wu Y" first="Yan" last="Wu">Yan Wu</name>
</country>
<country name="Canada"><noRegion><name sortKey="Mohan, Sankar" sort="Mohan, Sankar" uniqKey="Mohan S" first="Sankar" last="Mohan">Sankar Mohan</name>
</noRegion>
<name sortKey="Pinto, B Mario" sort="Pinto, B Mario" uniqKey="Pinto B" first="B. Mario" last="Pinto">B. Mario Pinto</name>
</country>
</tree>
</affiliations>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Ncbi/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000D07 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Checkpoint/biblio.hfd -nk 000D07 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= H2N2V1 |flux= Ncbi |étape= Checkpoint |type= RBID |clé= PMC:5110174 |texte= Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Checkpoint/RBID.i -Sk "pubmed:27654293" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Checkpoint/biblio.hfd \ | NlmPubMed2Wicri -a H2N2V1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |