Discovery of Highly Potent Pinanamine-Based Inhibitors Against Amantadine- and Oseltamivir- resistant Influenza A Viruses
Identifieur interne : 000897 ( Pmc/Corpus ); précédent : 000896; suivant : 000898Discovery of Highly Potent Pinanamine-Based Inhibitors Against Amantadine- and Oseltamivir- resistant Influenza A Viruses
Auteurs : Xin Zhao ; Runfeng Li ; Yang Zhou ; Mengjie Xiao ; Chunlong Ma ; Zhongjin Yang ; Shaogao Zeng ; Qiuling Du ; Chunguang Yang ; Haiming Jiang ; Yanmei Hu ; Kefeng Wang ; Chris Ka Pun Mok ; Ping Sun ; Jianghong Dong ; Wei Cui ; Jun Wang ; Yaoquan Tu ; Zifeng Yang ; Wenhui HuSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2018.
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
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DOI: 10.1021/acs.jmedchem.8b00042
PubMed: 29799746
PubMed Central: 6496959
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">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><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></affiliation><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Li, Runfeng" sort="Li, Runfeng" uniqKey="Li R" first="Runfeng" last="Li">Runfeng Li</name><affiliation><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></affiliation></author><author><name sortKey="Zhou, Yang" sort="Zhou, Yang" uniqKey="Zhou Y" first="Yang" last="Zhou">Yang Zhou</name><affiliation><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></affiliation></author><author><name sortKey="Xiao, Mengjie" sort="Xiao, Mengjie" uniqKey="Xiao M" first="Mengjie" last="Xiao">Mengjie Xiao</name><affiliation><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></affiliation><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Ma, Chunlong" sort="Ma, Chunlong" uniqKey="Ma C" first="Chunlong" last="Ma">Chunlong Ma</name><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Yang, Zhongjin" sort="Yang, Zhongjin" uniqKey="Yang Z" first="Zhongjin" last="Yang">Zhongjin Yang</name><affiliation><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></affiliation></author><author><name sortKey="Zeng, Shaogao" sort="Zeng, Shaogao" uniqKey="Zeng S" first="Shaogao" last="Zeng">Shaogao Zeng</name><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Du, Qiuling" sort="Du, Qiuling" uniqKey="Du Q" first="Qiuling" last="Du">Qiuling Du</name><affiliation><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></affiliation></author><author><name sortKey="Yang, Chunguang" sort="Yang, Chunguang" uniqKey="Yang C" first="Chunguang" last="Yang">Chunguang Yang</name><affiliation><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></affiliation></author><author><name sortKey="Jiang, Haiming" sort="Jiang, Haiming" uniqKey="Jiang H" first="Haiming" last="Jiang">Haiming Jiang</name><affiliation><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></affiliation></author><author><name sortKey="Hu, Yanmei" sort="Hu, Yanmei" uniqKey="Hu Y" first="Yanmei" last="Hu">Yanmei Hu</name><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Wang, Kefeng" sort="Wang, Kefeng" uniqKey="Wang K" first="Kefeng" last="Wang">Kefeng Wang</name><affiliation><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></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><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></affiliation><affiliation><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></affiliation></author><author><name sortKey="Sun, Ping" sort="Sun, Ping" uniqKey="Sun P" first="Ping" last="Sun">Ping Sun</name><affiliation><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></affiliation></author><author><name sortKey="Dong, Jianghong" sort="Dong, Jianghong" uniqKey="Dong J" first="Jianghong" last="Dong">Jianghong Dong</name><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Cui, Wei" sort="Cui, Wei" uniqKey="Cui W" first="Wei" last="Cui">Wei Cui</name><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Tu, Yaoquan" sort="Tu, Yaoquan" uniqKey="Tu Y" first="Yaoquan" last="Tu">Yaoquan Tu</name><affiliation><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></affiliation></author><author><name sortKey="Yang, Zifeng" sort="Yang, Zifeng" uniqKey="Yang Z" first="Zifeng" last="Yang">Zifeng Yang</name><affiliation><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></affiliation></author><author><name sortKey="Hu, Wenhui" sort="Hu, Wenhui" uniqKey="Hu W" first="Wenhui" last="Hu">Wenhui Hu</name><affiliation><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></affiliation><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></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></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><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></affiliation><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Li, Runfeng" sort="Li, Runfeng" uniqKey="Li R" first="Runfeng" last="Li">Runfeng Li</name><affiliation><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></affiliation></author><author><name sortKey="Zhou, Yang" sort="Zhou, Yang" uniqKey="Zhou Y" first="Yang" last="Zhou">Yang Zhou</name><affiliation><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></affiliation></author><author><name sortKey="Xiao, Mengjie" sort="Xiao, Mengjie" uniqKey="Xiao M" first="Mengjie" last="Xiao">Mengjie Xiao</name><affiliation><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></affiliation><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Ma, Chunlong" sort="Ma, Chunlong" uniqKey="Ma C" first="Chunlong" last="Ma">Chunlong Ma</name><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Yang, Zhongjin" sort="Yang, Zhongjin" uniqKey="Yang Z" first="Zhongjin" last="Yang">Zhongjin Yang</name><affiliation><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></affiliation></author><author><name sortKey="Zeng, Shaogao" sort="Zeng, Shaogao" uniqKey="Zeng S" first="Shaogao" last="Zeng">Shaogao Zeng</name><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Du, Qiuling" sort="Du, Qiuling" uniqKey="Du Q" first="Qiuling" last="Du">Qiuling Du</name><affiliation><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></affiliation></author><author><name sortKey="Yang, Chunguang" sort="Yang, Chunguang" uniqKey="Yang C" first="Chunguang" last="Yang">Chunguang Yang</name><affiliation><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></affiliation></author><author><name sortKey="Jiang, Haiming" sort="Jiang, Haiming" uniqKey="Jiang H" first="Haiming" last="Jiang">Haiming Jiang</name><affiliation><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></affiliation></author><author><name sortKey="Hu, Yanmei" sort="Hu, Yanmei" uniqKey="Hu Y" first="Yanmei" last="Hu">Yanmei Hu</name><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Wang, Kefeng" sort="Wang, Kefeng" uniqKey="Wang K" first="Kefeng" last="Wang">Kefeng Wang</name><affiliation><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></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><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></affiliation><affiliation><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></affiliation></author><author><name sortKey="Sun, Ping" sort="Sun, Ping" uniqKey="Sun P" first="Ping" last="Sun">Ping Sun</name><affiliation><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></affiliation></author><author><name sortKey="Dong, Jianghong" sort="Dong, Jianghong" uniqKey="Dong J" first="Jianghong" last="Dong">Jianghong Dong</name><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Cui, Wei" sort="Cui, Wei" uniqKey="Cui W" first="Wei" last="Cui">Wei Cui</name><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></affiliation></author><author><name sortKey="Wang, Jun" sort="Wang, Jun" uniqKey="Wang J" first="Jun" last="Wang">Jun Wang</name><affiliation><nlm:aff id="A4">Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation><affiliation><nlm:aff id="A5">BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</nlm:aff></affiliation></author><author><name sortKey="Tu, Yaoquan" sort="Tu, Yaoquan" uniqKey="Tu Y" first="Yaoquan" last="Tu">Yaoquan Tu</name><affiliation><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></affiliation></author><author><name sortKey="Yang, Zifeng" sort="Yang, Zifeng" uniqKey="Yang Z" first="Zifeng" last="Yang">Zifeng Yang</name><affiliation><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></affiliation></author><author><name sortKey="Hu, Wenhui" sort="Hu, Wenhui" uniqKey="Hu W" first="Wenhui" last="Hu">Wenhui Hu</name><affiliation><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></affiliation><affiliation><nlm:aff id="A2">Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</nlm:aff></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></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><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9716531</journal-id><journal-id journal-id-type="pubmed-jr-id">4938</journal-id><journal-id journal-id-type="nlm-ta">J Med Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Med. Chem.</journal-id><journal-title-group><journal-title>Journal of medicinal chemistry</journal-title></journal-title-group><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn></journal-meta><article-meta><article-id pub-id-type="pmid">29799746</article-id><article-id pub-id-type="pmc">6496959</article-id><article-id pub-id-type="doi">10.1021/acs.jmedchem.8b00042</article-id><article-id pub-id-type="manuscript">NIHMS1017109</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Discovery of Highly Potent Pinanamine-Based Inhibitors Against Amantadine- and Oseltamivir- resistant Influenza A Viruses</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Xin</given-names></name><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-6659-3748</contrib-id><xref ref-type="aff" rid="A1">†</xref><xref ref-type="aff" rid="A2">‖</xref><xref ref-type="aff" rid="A4">§</xref><xref rid="FN1" ref-type="author-notes">‡</xref><xref rid="CR1" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Runfeng</given-names></name><xref ref-type="aff" rid="A3">⊥</xref><xref rid="FN1" ref-type="author-notes">‡</xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Yang</given-names></name><xref ref-type="aff" rid="A6">#</xref><xref rid="FN1" ref-type="author-notes">‡</xref></contrib><contrib contrib-type="author"><name><surname>Xiao</surname><given-names>Mengjie</given-names></name><xref rid="FN1" ref-type="author-notes">‡</xref><xref ref-type="aff" rid="A1">†</xref><xref ref-type="aff" rid="A2">‖</xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Chunlong</given-names></name><xref ref-type="aff" rid="A4">§</xref><xref ref-type="aff" rid="A5">Δ</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Zhongjin</given-names></name><xref ref-type="aff" rid="A1">†</xref></contrib><contrib contrib-type="author"><name><surname>Zeng</surname><given-names>Shaogao</given-names></name><xref ref-type="aff" rid="A2">‖</xref></contrib><contrib contrib-type="author"><name><surname>Du</surname><given-names>Qiuling</given-names></name><xref ref-type="aff" rid="A3">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Chunguang</given-names></name><xref ref-type="aff" rid="A3">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Haiming</given-names></name><xref ref-type="aff" rid="A3">⊥</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Yanmei</given-names></name><xref ref-type="aff" rid="A4">§</xref><xref ref-type="aff" rid="A5">Δ</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Kefeng</given-names></name><xref ref-type="aff" rid="A1">†</xref></contrib><contrib contrib-type="author"><name><surname>Mok</surname><given-names>Chris Ka Pun</given-names></name><xref ref-type="aff" rid="A3">⊥</xref><xref ref-type="aff" rid="A7">▽</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Ping</given-names></name><xref ref-type="aff" rid="A1">†</xref></contrib><contrib contrib-type="author"><name><surname>Dong</surname><given-names>Jianghong</given-names></name><xref ref-type="aff" rid="A2">‖</xref></contrib><contrib contrib-type="author"><name><surname>Cui</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="A2">‖</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Jun</given-names></name><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-4845-4621</contrib-id><xref ref-type="aff" rid="A4">§</xref><xref ref-type="aff" rid="A5">Δ</xref></contrib><contrib contrib-type="author"><name><surname>Tu</surname><given-names>Yaoquan</given-names></name><xref ref-type="aff" rid="A6">#</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Zifeng</given-names></name><xref ref-type="aff" rid="A3">⊥</xref><xref rid="CR2" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Wenhui</given-names></name><xref ref-type="aff" rid="A1">†</xref><xref ref-type="aff" rid="A2">‖</xref><xref rid="CR3" ref-type="corresp">*</xref></contrib></contrib-group><aff id="A1"><label>†</label>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</aff><aff id="A2"><label>‖</label>Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, P.R. China</aff><aff id="A3"><label>⊥</label>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</aff><aff id="A4"><label>§</label>Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States</aff><aff id="A5"><label>Δ</label>BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States</aff><aff id="A6"><label>#</label>Division of Theoretical Chemistry and Biology, School of Biotechnology, Royal Institute of Technology (KTH), AlbaNova University Center, Stockholm SE-100 44, Sweden</aff><aff id="A7"><label>▽</label>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</aff><author-notes><fn fn-type="other" id="FN1"><label>‡</label><p id="P1">These authors contributed equally.</p></fn><fn fn-type="con" id="FN2"><p id="P2">Author Contributions</p><p id="P3">The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.</p></fn><corresp id="CR1"><label>*</label><bold>Corresponding Author</bold><email>zhaoxin2017@foxmail.com</email></corresp><corresp id="CR2"><label>*</label><email>jeffyah@163.com</email></corresp><corresp id="CR3"><label>*</label><email>huwenhui@gzhmu.edu.cn</email></corresp><fn fn-type="COI-statement" id="FN4"><p id="P63">The authors declare no competing financial interest.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>24</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>11</day><month>6</month><year>2018</year></pub-date><pub-date pub-type="ppub"><day>28</day><month>6</month><year>2018</year></pub-date><pub-date pub-type="pmc-release"><day>02</day><month>5</month><year>2019</year></pub-date><volume>61</volume><issue>12</issue><fpage>5187</fpage><lpage>5198</lpage><pmc-comment>elocation-id from pubmed: 10.1021/acs.jmedchem.8b00042</pmc-comment>
<abstract id="ABS1"><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></abstract><abstract abstract-type="graphical" id="ABS2"><title>SYNOPSIS</title><p id="P6"><graphic xlink:href="nihms-1017109-f0009.jpg" position="anchor" orientation="portrait"></graphic></p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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