Discovery of Highly Potent Pinanamine-Based Inhibitors Against Amantadine- and Oseltamivir- resistant Influenza A Viruses
Identifieur interne : 000540 ( Main/Exploration ); précédent : 000539; suivant : 000541Discovery of Highly Potent Pinanamine-Based Inhibitors Against Amantadine- and Oseltamivir- resistant Influenza A Viruses
Auteurs : Xin Zhao [République populaire de Chine, États-Unis] ; Runfeng Li [République populaire de Chine] ; Yang Zhou [Suède] ; Mengjie Xiao [République populaire de Chine] ; Chunlong Ma [États-Unis] ; Zhongjin Yang [République populaire de Chine] ; Shaogao Zeng [République populaire de Chine] ; Qiuling Du [République populaire de Chine] ; Chunguang Yang [République populaire de Chine] ; Haiming Jiang [République populaire de Chine] ; Yanmei Hu [États-Unis] ; Kefeng Wang [République populaire de Chine] ; Chris Ka Pun Mok [République populaire de Chine, Hong Kong] ; Ping Sun [République populaire de Chine] ; Jianghong Dong [République populaire de Chine] ; Wei Cui [République populaire de Chine] ; Jun Wang [États-Unis] ; Yaoquan Tu [Suède] ; Zifeng Yang [République populaire de Chine] ; Wenhui Hu [République populaire de Chine]Source :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2018.
Descripteurs français
- KwdFr :
- Amantadine (), Amantadine (pharmacologie), Antienzymes (), Antienzymes (pharmacologie), Antiviraux (), Antiviraux (pharmacologie), Conformation moléculaire, Découverte de médicament, Hémagglutinines (métabolisme), Imidazoles (), Imidazoles (pharmacologie), Oséltamivir (), Oséltamivir (pharmacologie), Relation dose-effet des médicaments, Relation structure-activité, Résistance virale aux médicaments (), Sialidase (antagonistes et inhibiteurs), Sialidase (métabolisme), Tests de sensibilité microbienne, Virus de la grippe A (), Virus de la grippe A (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Sialidase.
- enzymologie : Virus de la grippe A.
- métabolisme : Hémagglutinines, Sialidase.
- pharmacologie : Amantadine, Antienzymes, Antiviraux, Imidazoles, Oséltamivir.
- Amantadine, Antienzymes, Antiviraux, Conformation moléculaire, Découverte de médicament, Imidazoles, Oséltamivir, Relation dose-effet des médicaments, Relation structure-activité, Résistance virale aux médicaments, Tests de sensibilité microbienne, Virus de la grippe A.
English descriptors
- KwdEn :
- Amantadine (chemistry), Amantadine (pharmacology), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Dose-Response Relationship, Drug, Drug Discovery, Drug Resistance, Viral (drug effects), Enzyme Inhibitors (chemistry), Enzyme Inhibitors (pharmacology), Hemagglutinins (metabolism), Imidazoles (chemistry), Imidazoles (pharmacology), Influenza A virus (drug effects), Influenza A virus (enzymology), Microbial Sensitivity Tests, Molecular Conformation, Neuraminidase (antagonists & inhibitors), Neuraminidase (metabolism), Oseltamivir (chemistry), Oseltamivir (pharmacology), Structure-Activity Relationship.
- MESH :
- chemical , antagonists & inhibitors : Neuraminidase.
- chemical , chemistry : Amantadine, Antiviral Agents, Enzyme Inhibitors, Imidazoles, Oseltamivir.
- chemical , metabolism : Hemagglutinins, Neuraminidase.
- chemical , pharmacology : Amantadine, Antiviral Agents, Enzyme Inhibitors, Imidazoles, Oseltamivir.
- drug effects : Drug Resistance, Viral, Influenza A virus.
- enzymology : Influenza A virus.
- Dose-Response Relationship, Drug, Drug Discovery, Microbial Sensitivity Tests, Molecular Conformation, Structure-Activity Relationship.
Abstract
Influenza pandemic is a constant major threat to public health caused by influenza A viruses (IAV). IAVs are sub-categorized by the surface proteins: hemagglutinin (HA) and neuraminidase (NA), in which they are both essential targets for drug discovery. While it is of great concern that NA inhibitor oseltamivir resistant strains are frequently identified from human or avian influenza virus, structural and functional characterization of influenza HA has raised hopes for new antiviral therapies. In this study, we explored a structure-activity relationship (SAR) of pinanamine-based antivirals and discovered a potent inhibitor
Url:
DOI: 10.1021/acs.jmedchem.8b00042
PubMed: 29799746
PubMed Central: 6496959
Affiliations:
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Le document en format XML
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China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Dong, Jianghong" sort="Dong, Jianghong" uniqKey="Dong J" first="Jianghong" last="Dong">Jianghong Dong</name><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Cui, Wei" sort="Cui, Wei" uniqKey="Cui W" first="Wei" last="Cui">Wei Cui</name><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>BIO5 Institute, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation></author><author><name sortKey="Tu, Yaoquan" sort="Tu, Yaoquan" uniqKey="Tu Y" first="Yaoquan" last="Tu">Yaoquan Tu</name><affiliation wicri:level="1"><nlm:aff id="A6">Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44</wicri:regionArea><wicri:noRegion>Stockholm SE-100 44</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Zifeng" sort="Yang, Zifeng" uniqKey="Yang Z" first="Zifeng" last="Yang">Zifeng Yang</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Hu, Wenhui" sort="Hu, Wenhui" uniqKey="Hu W" first="Wenhui" last="Hu">Wenhui Hu</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29799746</idno><idno type="pmc">6496959</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496959</idno><idno type="RBID">PMC:6496959</idno><idno type="doi">10.1021/acs.jmedchem.8b00042</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000897</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000897</idno><idno type="wicri:Area/Pmc/Curation">000897</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000897</idno><idno type="wicri:Area/Pmc/Checkpoint">000158</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000158</idno><idno type="wicri:source">PubMed</idno><idno type="RBID">pubmed:29799746</idno><idno type="wicri:Area/PubMed/Corpus">000291</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000291</idno><idno type="wicri:Area/PubMed/Curation">000291</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000291</idno><idno type="wicri:Area/PubMed/Checkpoint">000294</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000294</idno><idno type="wicri:Area/Ncbi/Merge">001E00</idno><idno type="wicri:Area/Ncbi/Curation">001E00</idno><idno type="wicri:Area/Ncbi/Checkpoint">001E00</idno><idno type="wicri:doubleKey">0022-2623:2018:Zhao X:discovery:of:highly</idno><idno type="wicri:Area/Main/Merge">000540</idno><idno type="wicri:Area/Main/Curation">000540</idno><idno type="wicri:Area/Main/Exploration">000540</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Discovery of Highly Potent Pinanamine-Based Inhibitors Against Amantadine- and Oseltamivir- resistant Influenza A Viruses</title><author><name sortKey="Zhao, Xin" sort="Zhao, Xin" uniqKey="Zhao X" first="Xin" last="Zhao">Xin Zhao</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation></author><author><name sortKey="Li, Runfeng" sort="Li, Runfeng" uniqKey="Li R" first="Runfeng" last="Li">Runfeng Li</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zhou, Yang" sort="Zhou, Yang" uniqKey="Zhou Y" first="Yang" last="Zhou">Yang Zhou</name><affiliation wicri:level="1"><nlm:aff id="A6">Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44</wicri:regionArea><wicri:noRegion>Stockholm SE-100 44</wicri:noRegion></affiliation></author><author><name sortKey="Xiao, Mengjie" sort="Xiao, Mengjie" uniqKey="Xiao M" first="Mengjie" last="Xiao">Mengjie Xiao</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Ma, Chunlong" sort="Ma, Chunlong" uniqKey="Ma C" first="Chunlong" last="Ma">Chunlong Ma</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>BIO5 Institute, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Zhongjin" sort="Yang, Zhongjin" uniqKey="Yang Z" first="Zhongjin" last="Yang">Zhongjin Yang</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Zeng, Shaogao" sort="Zeng, Shaogao" uniqKey="Zeng S" first="Shaogao" last="Zeng">Shaogao Zeng</name><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Du, Qiuling" sort="Du, Qiuling" uniqKey="Du Q" first="Qiuling" last="Du">Qiuling Du</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Yang, Chunguang" sort="Yang, Chunguang" uniqKey="Yang C" first="Chunguang" last="Yang">Chunguang Yang</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Jiang, Haiming" sort="Jiang, Haiming" uniqKey="Jiang H" first="Haiming" last="Jiang">Haiming Jiang</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Hu, Yanmei" sort="Hu, Yanmei" uniqKey="Hu Y" first="Yanmei" last="Hu">Yanmei Hu</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>BIO5 Institute, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Kefeng" sort="Wang, Kefeng" uniqKey="Wang K" first="Kefeng" last="Wang">Kefeng Wang</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Mok, Chris Ka Pun" sort="Mok, Chris Ka Pun" uniqKey="Mok C" first="Chris Ka Pun" last="Mok">Chris Ka Pun Mok</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A7">HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, 5 Sassoon Road, Hong Kong</nlm:aff><country xml:lang="fr">Hong Kong</country><wicri:regionArea>HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, 5 Sassoon Road</wicri:regionArea><wicri:noRegion>5 Sassoon Road</wicri:noRegion></affiliation></author><author><name sortKey="Sun, Ping" sort="Sun, Ping" uniqKey="Sun P" first="Ping" last="Sun">Ping Sun</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Dong, Jianghong" sort="Dong, Jianghong" uniqKey="Dong J" first="Jianghong" last="Dong">Jianghong Dong</name><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Cui, Wei" sort="Cui, Wei" uniqKey="Cui W" first="Wei" last="Cui">Wei Cui</name><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>BIO5 Institute, The University of Arizona, Tucson, Arizona 85721</wicri:regionArea><wicri:noRegion>Arizona 85721</wicri:noRegion></affiliation></author><author><name sortKey="Tu, Yaoquan" sort="Tu, Yaoquan" uniqKey="Tu Y" first="Yaoquan" last="Tu">Yaoquan Tu</name><affiliation wicri:level="1"><nlm:aff id="A6">Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44, Sweden</nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44</wicri:regionArea><wicri:noRegion>Stockholm SE-100 44</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Zifeng" sort="Yang, Zifeng" uniqKey="Yang Z" first="Zifeng" last="Yang">Zifeng Yang</name><affiliation wicri:level="1"><nlm:aff id="A3">State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou 510120</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author><author><name sortKey="Hu, Wenhui" sort="Hu, Wenhui" uniqKey="Hu W" first="Wenhui" last="Hu">Wenhui Hu</name><affiliation wicri:level="1"><nlm:aff id="A1">State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530</wicri:regionArea><placeName><settlement type="city">Jiangmen</settlement><region type="province">Guangdong</region></placeName></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="ISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amantadine (chemistry)</term><term>Amantadine (pharmacology)</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Dose-Response Relationship, Drug</term><term>Drug Discovery</term><term>Drug Resistance, Viral (drug effects)</term><term>Enzyme Inhibitors (chemistry)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Hemagglutinins (metabolism)</term><term>Imidazoles (chemistry)</term><term>Imidazoles (pharmacology)</term><term>Influenza A virus (drug effects)</term><term>Influenza A virus (enzymology)</term><term>Microbial Sensitivity Tests</term><term>Molecular Conformation</term><term>Neuraminidase (antagonists & inhibitors)</term><term>Neuraminidase (metabolism)</term><term>Oseltamivir (chemistry)</term><term>Oseltamivir (pharmacology)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Amantadine ()</term><term>Amantadine (pharmacologie)</term><term>Antienzymes ()</term><term>Antienzymes (pharmacologie)</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Conformation moléculaire</term><term>Découverte de médicament</term><term>Hémagglutinines (métabolisme)</term><term>Imidazoles ()</term><term>Imidazoles (pharmacologie)</term><term>Oséltamivir ()</term><term>Oséltamivir (pharmacologie)</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Résistance virale aux médicaments ()</term><term>Sialidase (antagonistes et inhibiteurs)</term><term>Sialidase (métabolisme)</term><term>Tests de sensibilité microbienne</term><term>Virus de la grippe A ()</term><term>Virus de la grippe A (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Neuraminidase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amantadine</term><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>Imidazoles</term><term>Oseltamivir</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Hemagglutinins</term><term>Neuraminidase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amantadine</term><term>Antiviral Agents</term><term>Enzyme Inhibitors</term><term>Imidazoles</term><term>Oseltamivir</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Sialidase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Drug Resistance, Viral</term><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Hémagglutinines</term><term>Sialidase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Amantadine</term><term>Antienzymes</term><term>Antiviraux</term><term>Imidazoles</term><term>Oséltamivir</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term><term>Drug Discovery</term><term>Microbial Sensitivity Tests</term><term>Molecular Conformation</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Amantadine</term><term>Antienzymes</term><term>Antiviraux</term><term>Conformation moléculaire</term><term>Découverte de médicament</term><term>Imidazoles</term><term>Oséltamivir</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Résistance virale aux médicaments</term><term>Tests de sensibilité microbienne</term><term>Virus de la grippe A</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p id="P4">Influenza pandemic is a constant major threat to public health caused by influenza A viruses (IAV). IAVs are sub-categorized by the surface proteins: hemagglutinin (HA) and neuraminidase (NA), in which they are both essential targets for drug discovery. While it is of great concern that NA inhibitor oseltamivir resistant strains are frequently identified from human or avian influenza virus, structural and functional characterization of influenza HA has raised hopes for new antiviral therapies. In this study, we explored a structure-activity relationship (SAR) of pinanamine-based antivirals and discovered a potent inhibitor <bold>M090</bold> against amantadine-resistant viruses, including the 2009 H1N1 pandemic strains, and oseltamivir- resistant viruses. Mechanism of action studies, particularly hemolysis inhibition, indicated that <bold>M090</bold> targets influenza HA and it occupied a highly conserved pocket of the HA<sub>2</sub> domain and inhibited virus-mediated membrane fusion by “locking” the bending state of HA<sub>2</sub> during the conformational rearrangement process. This work provides new binding sites within the HA protein and indicates that this pocket may be a promising target for broad-spectrum anti-influenza A drug design and development.</p></div></front></TEI><affiliations><list><country><li>Hong Kong</li><li>République populaire de Chine</li><li>Suède</li><li>États-Unis</li></country><region><li>Guangdong</li></region><settlement><li>Jiangmen</li></settlement></list><tree><country name="République populaire de Chine"><region name="Guangdong"><name sortKey="Zhao, Xin" sort="Zhao, Xin" uniqKey="Zhao X" first="Xin" last="Zhao">Xin Zhao</name></region><name sortKey="Cui, Wei" sort="Cui, Wei" uniqKey="Cui W" first="Wei" last="Cui">Wei Cui</name><name sortKey="Dong, Jianghong" sort="Dong, Jianghong" uniqKey="Dong J" first="Jianghong" last="Dong">Jianghong Dong</name><name sortKey="Du, Qiuling" sort="Du, Qiuling" uniqKey="Du Q" first="Qiuling" last="Du">Qiuling Du</name><name sortKey="Hu, Wenhui" sort="Hu, Wenhui" uniqKey="Hu W" first="Wenhui" last="Hu">Wenhui Hu</name><name sortKey="Hu, Wenhui" sort="Hu, Wenhui" uniqKey="Hu W" first="Wenhui" last="Hu">Wenhui Hu</name><name sortKey="Jiang, Haiming" sort="Jiang, Haiming" uniqKey="Jiang H" first="Haiming" last="Jiang">Haiming Jiang</name><name sortKey="Li, Runfeng" sort="Li, Runfeng" uniqKey="Li R" first="Runfeng" last="Li">Runfeng Li</name><name sortKey="Mok, Chris Ka Pun" sort="Mok, Chris Ka Pun" uniqKey="Mok C" first="Chris Ka Pun" last="Mok">Chris Ka Pun Mok</name><name sortKey="Sun, Ping" sort="Sun, Ping" uniqKey="Sun P" first="Ping" last="Sun">Ping Sun</name><name sortKey="Wang, Kefeng" sort="Wang, Kefeng" uniqKey="Wang K" first="Kefeng" last="Wang">Kefeng Wang</name><name sortKey="Xiao, Mengjie" sort="Xiao, Mengjie" uniqKey="Xiao M" first="Mengjie" last="Xiao">Mengjie Xiao</name><name sortKey="Xiao, Mengjie" sort="Xiao, Mengjie" uniqKey="Xiao M" first="Mengjie" last="Xiao">Mengjie Xiao</name><name sortKey="Yang, Chunguang" sort="Yang, Chunguang" uniqKey="Yang C" first="Chunguang" last="Yang">Chunguang Yang</name><name sortKey="Yang, Zhongjin" sort="Yang, Zhongjin" uniqKey="Yang Z" first="Zhongjin" last="Yang">Zhongjin Yang</name><name sortKey="Yang, Zifeng" sort="Yang, Zifeng" uniqKey="Yang Z" first="Zifeng" last="Yang">Zifeng Yang</name><name sortKey="Zeng, Shaogao" sort="Zeng, Shaogao" uniqKey="Zeng S" first="Shaogao" last="Zeng">Shaogao Zeng</name><name sortKey="Zhao, Xin" sort="Zhao, Xin" uniqKey="Zhao X" first="Xin" last="Zhao">Xin Zhao</name></country><country name="États-Unis"><noRegion><name sortKey="Zhao, Xin" sort="Zhao, Xin" uniqKey="Zhao X" first="Xin" last="Zhao">Xin Zhao</name></noRegion><name sortKey="Hu, Yanmei" sort="Hu, Yanmei" uniqKey="Hu Y" first="Yanmei" last="Hu">Yanmei Hu</name><name sortKey="Hu, Yanmei" sort="Hu, Yanmei" uniqKey="Hu Y" first="Yanmei" last="Hu">Yanmei Hu</name><name sortKey="Ma, Chunlong" sort="Ma, Chunlong" uniqKey="Ma C" first="Chunlong" last="Ma">Chunlong Ma</name><name sortKey="Ma, Chunlong" sort="Ma, Chunlong" uniqKey="Ma C" first="Chunlong" last="Ma">Chunlong Ma</name><name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name><name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name></country><country name="Suède"><noRegion><name sortKey="Zhou, Yang" sort="Zhou, Yang" uniqKey="Zhou Y" first="Yang" last="Zhou">Yang Zhou</name></noRegion><name sortKey="Tu, Yaoquan" sort="Tu, Yaoquan" uniqKey="Tu Y" first="Yaoquan" last="Tu">Yaoquan Tu</name></country><country name="Hong Kong"><noRegion><name sortKey="Mok, Chris Ka Pun" sort="Mok, Chris Ka Pun" uniqKey="Mok C" first="Chris Ka Pun" last="Mok">Chris Ka Pun Mok</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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