Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury
Identifieur interne : 000126 ( Pmc/Checkpoint ); précédent : 000125; suivant : 000127Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury
Auteurs : Fengming Huang [République populaire de Chine] ; Cong Zhang [République populaire de Chine] ; Qiang Liu [République populaire de Chine] ; Yan Zhao [République populaire de Chine] ; Yuqing Zhang [République populaire de Chine] ; Yuhao Qin [République populaire de Chine] ; Xiao Li [République populaire de Chine] ; Chang Li [République populaire de Chine] ; Congzhao Zhou [République populaire de Chine] ; Ningyi Jin [République populaire de Chine] ; Chengyu Jiang [République populaire de Chine]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2020.
Abstract
Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre- and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an anti-neoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.
Url:
DOI: 10.1371/journal.ppat.1008341
PubMed: 32176725
PubMed Central: 7075543
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Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhang, Yuqing" sort="Zhang, Yuqing" uniqKey="Zhang Y" first="Yuqing" last="Zhang">Yuqing Zhang</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Qin, Yuhao" sort="Qin, Yuhao" uniqKey="Qin Y" first="Yuhao" last="Qin">Yuhao Qin</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun</wicri:regionArea><placeName><settlement type="city">Changchun</settlement><region type="province">Jilin</region><region type="groupement">Dongbei</region></placeName></affiliation></author><author><name sortKey="Li, Chang" sort="Li, Chang" uniqKey="Li C" first="Chang" last="Li">Chang Li</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun</wicri:regionArea><placeName><settlement type="city">Changchun</settlement><region type="province">Jilin</region><region type="groupement">Dongbei</region></placeName></affiliation></author><author><name sortKey="Zhou, Congzhao" sort="Zhou, Congzhao" uniqKey="Zhou C" first="Congzhao" last="Zhou">Congzhao Zhou</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui</wicri:regionArea><wicri:noRegion>Anhui</wicri:noRegion></affiliation></author><author><name sortKey="Jin, Ningyi" sort="Jin, Ningyi" uniqKey="Jin N" first="Ningyi" last="Jin">Ningyi Jin</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun</wicri:regionArea><placeName><settlement type="city">Changchun</settlement><region type="province">Jilin</region><region 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uniqKey="Huang F" first="Fengming" last="Huang">Fengming Huang</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui</wicri:regionArea><wicri:noRegion>Anhui</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhang, Cong" sort="Zhang, Cong" uniqKey="Zhang C" first="Cong" last="Zhang">Cong Zhang</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui</wicri:regionArea><wicri:noRegion>Anhui</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Liu, Qiang" sort="Liu, Qiang" uniqKey="Liu Q" first="Qiang" last="Liu">Qiang Liu</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhao, Yan" sort="Zhao, Yan" uniqKey="Zhao Y" first="Yan" last="Zhao">Yan Zhao</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Zhang, Yuqing" sort="Zhang, Yuqing" uniqKey="Zhang Y" first="Yuqing" last="Zhang">Yuqing Zhang</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Qin, Yuhao" sort="Qin, Yuhao" uniqKey="Qin Y" first="Yuhao" last="Qin">Yuhao Qin</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author><author><name sortKey="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun</wicri:regionArea><placeName><settlement type="city">Changchun</settlement><region type="province">Jilin</region><region type="groupement">Dongbei</region></placeName></affiliation></author><author><name sortKey="Li, Chang" sort="Li, Chang" uniqKey="Li C" first="Chang" last="Li">Chang Li</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun</wicri:regionArea><placeName><settlement type="city">Changchun</settlement><region type="province">Jilin</region><region type="groupement">Dongbei</region></placeName></affiliation></author><author><name sortKey="Zhou, Congzhao" sort="Zhou, Congzhao" uniqKey="Zhou C" first="Congzhao" last="Zhou">Congzhao Zhou</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui</wicri:regionArea><wicri:noRegion>Anhui</wicri:noRegion></affiliation></author><author><name sortKey="Jin, Ningyi" sort="Jin, Ningyi" uniqKey="Jin N" first="Ningyi" last="Jin">Ningyi Jin</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun</wicri:regionArea><placeName><settlement type="city">Changchun</settlement><region type="province">Jilin</region><region type="groupement">Dongbei</region></placeName></affiliation></author><author><name sortKey="Jiang, Chengyu" sort="Jiang, Chengyu" uniqKey="Jiang C" first="Chengyu" last="Jiang">Chengyu Jiang</name><affiliation wicri:level="3"><nlm:aff id="aff002"><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing</wicri:regionArea><placeName><settlement type="city">Pékin</settlement></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre- and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an anti-neoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Van Norman, Ga" uniqKey="Van Norman G">GA Van Norman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nosengo, N" uniqKey="Nosengo N">N Nosengo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bauer, Tt" uniqKey="Bauer T">TT Bauer</name></author><author><name sortKey="Ewig, S" uniqKey="Ewig S">S Ewig</name></author><author><name sortKey="Rodloff, Ac" uniqKey="Rodloff A">AC Rodloff</name></author><author><name sortKey="Muller, Ee" uniqKey="Muller E">EE Muller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plospath</journal-id><journal-title-group><journal-title>PLoS Pathogens</journal-title></journal-title-group><issn pub-type="ppub">1553-7366</issn><issn pub-type="epub">1553-7374</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32176725</article-id><article-id pub-id-type="pmc">7075543</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1008341</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-19-02141</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>RNA viruses</subject><subj-group><subject>Orthomyxoviruses</subject><subj-group><subject>Influenza viruses</subject><subj-group><subject>Influenza A virus</subject><subj-group><subject>H5N1</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical microbiology</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Orthomyxoviruses</subject><subj-group><subject>Influenza viruses</subject><subj-group><subject>Influenza A virus</subject><subj-group><subject>H5N1</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject><subj-group><subject>Pathology and laboratory medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Orthomyxoviruses</subject><subj-group><subject>Influenza viruses</subject><subj-group><subject>Influenza A virus</subject><subj-group><subject>H5N1</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Orthomyxoviruses</subject><subj-group><subject>Influenza viruses</subject><subj-group><subject>Influenza A virus</subject><subj-group><subject>H5N1</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Infectious Diseases</subject><subj-group><subject>Zoonoses</subject><subj-group><subject>H5N1</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmaceutics</subject><subj-group><subject>Drug Therapy</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmaceutics</subject><subj-group><subject>Drug Therapy</subject><subj-group><subject>Drug Administration</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmacology</subject><subj-group><subject>Drug Screening</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Hormones</subject><subj-group><subject>Lipid Hormones</subject><subj-group><subject>Calcitriol</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Oncology</subject><subj-group><subject>Cancers and Neoplasms</subject><subj-group><subject>Lung and Intrathoracic Tumors</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Developmental Biology</subject><subj-group><subject>Organism Development</subject><subj-group><subject>Organogenesis</subject><subj-group><subject>Lung Development</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmacology</subject><subj-group><subject>Drug Research and Development</subject><subj-group><subject>Drug Discovery</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury</article-title><alt-title alt-title-type="running-head">Identification of 4 drugs as repurposing drugs for influenza A H5N1 virus-induced lung injury</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Huang</surname><given-names>Fengming</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Zhang</surname><given-names>Cong</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-6343-8080</contrib-id><name><surname>Liu</surname><given-names>Qiang</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Yan</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Supervision</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Yuqing</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Qin</surname><given-names>Yuhao</given-names></name><role content-type="http://credit.casrai.org/">Investigation</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Xiao</given-names></name><role content-type="http://credit.casrai.org/">Validation</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Chang</given-names></name><role content-type="http://credit.casrai.org/">Validation</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Congzhao</given-names></name><role content-type="http://credit.casrai.org/">Supervision</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib><contrib contrib-type="author"><name><surname>Jin</surname><given-names>Ningyi</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Resources</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-0570-2709</contrib-id><name><surname>Jiang</surname><given-names>Chengyu</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China</addr-line></aff><aff id="aff002"><label>2</label><addr-line>State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Department of Biochemistry, School of Basic Medicine Peking Union Medical College, Beijing, China</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Genetic Engineering Laboratory, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Tripp</surname><given-names>Ralph A.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Georgia, UNITED STATES</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>zcz@ustc.edu.cn</email> (CZ); <email>ningyik@126.com</email> (NJ); <email>jiang@pumc.edu.cn</email> (CJ)</corresp></author-notes><pub-date pub-type="epub"><day>16</day><month>3</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>3</month><year>2020</year></pub-date><volume>16</volume><issue>3</issue><elocation-id>e1008341</elocation-id><history><date date-type="received"><day>15</day><month>11</month><year>2019</year></date><date date-type="accepted"><day>21</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 Huang et al</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>Huang et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="ppat.1008341.pdf"></self-uri><abstract><p>Infection with avian influenza A H5N1 virus results in acute lung injury (ALI) and has a high mortality rate (52.79%) because there are limited therapies available for treatment. Drug repositioning is an economical approach to drug discovery. We developed a method for drug repositioning based on high-throughput RNA sequencing and identified several drugs as potential treatments for avian influenza A H5N1 virus. Using high-throughput RNA sequencing, we identified a total of 1,233 genes differentially expressed in A549 cells upon H5N1 virus infection. Among these candidate genes, 79 drug targets (corresponding to 59 approved drugs) overlapped with the DrugBank target database. Twenty-two of the 41 commercially available small-molecule drugs reduced H5N1-mediated cell death in cultured A549 cells, and fifteen drugs that protected A549 cells when administered both pre- and post-infection were tested in an H5N1-infection mouse model. The results showed significant alleviation of acute lung injury by amitriptyline HCl (an antidepressant drug), flavin adenine dinucleotide (FAD; an ophthalmic agent for vitamin B2 deficiency), azacitidine (an anti-neoplastic drug) and calcitriol (an active form of vitamin D). All four agents significantly reduced the infiltrating cell count and decreased the lung injury score in H5N1 virus-infected mice based on lung histopathology, significantly improved mouse lung edema by reducing the wet-to-dry weight ratio of lung tissue and significantly improved the survival of H5N1 virus-infected mice. This study not only identifies novel potential therapies for influenza H5N1 virus-induced lung injury but also provides a highly effective and economical screening method for repurposing drugs that may be generalizable for the prevention and therapy of other diseases.</p></abstract><abstract abstract-type="summary"><title>Author summary</title><p>Highly pathogenic avian influenza (HPAI) A virus H5N1 causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), with mortality as high as 52.79%. No vaccine for HPAI virus is available, and current treatments for influenza A H5N1 virus-induced ALI have limitations. Drug repurposing may be an effective approach for developing novel therapeutic strategies. In this study, we identified 4 drugs, the antidepressant amitriptyline HCl, the ophthalmic flavin adenine dinucleotide, the anti-neoplastic azacitidine and the vitamin D-deficiency treatment calcitriol, as being highly effective for the treatment of H5N1 virus-induced ALI using a transcriptomic-based high-throughput repurposing drug screening. These approved drugs might constitute novel potential remedies for treating influenza H5N1 virus infection, and this screening method may be generalizable for drug repositioning to identify new indications for other diseases.</p></abstract><funding-group><award-group id="award001"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81788101</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-0570-2709</contrib-id><name><surname>Jiang</surname><given-names>Chengyu</given-names></name></principal-award-recipient></award-group><award-group id="award002"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81490531</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-0570-2709</contrib-id><name><surname>Jiang</surname><given-names>Chengyu</given-names></name></principal-award-recipient></award-group><award-group id="award003"><funding-source><institution-wrap><institution-id institution-id-type="funder-id">http://dx.doi.org/10.13039/501100002855</institution-id><institution>Ministry of Science and Technology of the People's Republic of China</institution></institution-wrap></funding-source><award-id>2015CB553406</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-0570-2709</contrib-id><name><surname>Jiang</surname><given-names>Chengyu</given-names></name></principal-award-recipient></award-group><award-group id="award004"><funding-source><institution>Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences</institution></funding-source><award-id>2017-I2M-1-009</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-0570-2709</contrib-id><name><surname>Jiang</surname><given-names>Chengyu</given-names></name></principal-award-recipient></award-group><funding-statement>This work was supported by the National Natural Science Foundation of China (grants 81788101, 81490531), the Ministry of Science and Technology of China (grant 2015CB553406), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2017-I2M-1-009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="4"></fig-count><table-count count="0"></table-count><page-count count="16"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>All relevant data are within the manuscript and its Supporting Information files.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>All relevant data are within the manuscript and its Supporting Information files.</p></notes></front></pmc><affiliations><list><country><li>République populaire de Chine</li></country><region><li>Dongbei</li><li>Jilin</li></region><settlement><li>Changchun</li><li>Pékin</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Huang, Fengming" sort="Huang, Fengming" uniqKey="Huang F" first="Fengming" last="Huang">Fengming Huang</name></noRegion><name sortKey="Huang, Fengming" sort="Huang, Fengming" uniqKey="Huang F" first="Fengming" last="Huang">Fengming Huang</name><name sortKey="Jiang, Chengyu" sort="Jiang, Chengyu" uniqKey="Jiang C" first="Chengyu" last="Jiang">Chengyu Jiang</name><name sortKey="Jin, Ningyi" sort="Jin, Ningyi" uniqKey="Jin N" first="Ningyi" last="Jin">Ningyi Jin</name><name sortKey="Li, Chang" sort="Li, Chang" uniqKey="Li C" first="Chang" last="Li">Chang Li</name><name sortKey="Li, Xiao" sort="Li, Xiao" uniqKey="Li X" first="Xiao" last="Li">Xiao Li</name><name sortKey="Liu, Qiang" sort="Liu, Qiang" uniqKey="Liu Q" first="Qiang" last="Liu">Qiang Liu</name><name sortKey="Qin, Yuhao" sort="Qin, Yuhao" uniqKey="Qin Y" first="Yuhao" last="Qin">Yuhao Qin</name><name sortKey="Zhang, Cong" sort="Zhang, Cong" uniqKey="Zhang C" first="Cong" last="Zhang">Cong Zhang</name><name sortKey="Zhang, Cong" sort="Zhang, Cong" uniqKey="Zhang C" first="Cong" last="Zhang">Cong Zhang</name><name sortKey="Zhang, Yuqing" sort="Zhang, Yuqing" uniqKey="Zhang Y" first="Yuqing" last="Zhang">Yuqing Zhang</name><name sortKey="Zhao, Yan" sort="Zhao, Yan" uniqKey="Zhao Y" first="Yan" last="Zhao">Yan Zhao</name><name sortKey="Zhou, Congzhao" sort="Zhou, Congzhao" uniqKey="Zhou C" first="Congzhao" last="Zhou">Congzhao Zhou</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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