Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63
Identifieur interne : 000647 ( Pmc/Checkpoint ); précédent : 000646; suivant : 000648Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63
Auteurs : Yu-Chi Tsai ; Chia-Lin Lee [Taïwan] ; Hung-Rong Yen [Taïwan] ; Young-Sheng Chang ; Yu-Ping Lin ; Su-Hua Huang ; Cheng-Wen LinSource :
- Biomolecules [ 2218-273X ] ; 2020.
Abstract
Url:
DOI: 10.3390/biom10030366
PubMed: 32120929
PubMed Central: 7175275
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Antiviral Action of Tryptanthrin Isolated from <italic>Strobilanthes cusia</italic> Leaf against Human Coronavirus NL63</title><author><name sortKey="Tsai, Yu Chi" sort="Tsai, Yu Chi" uniqKey="Tsai Y" first="Yu-Chi" last="Tsai">Yu-Chi Tsai</name><affiliation><nlm:aff id="af1-biomolecules-10-00366">PhD Program for Health Science and Industry, College of Health Care, China Medical University, Taichung 40402, Taiwan;<email>chijoan0805@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-10-00366">Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Lee, Chia Lin" sort="Lee, Chia Lin" uniqKey="Lee C" first="Chia-Lin" last="Lee">Chia-Lin Lee</name><affiliation><nlm:aff id="af4-biomolecules-10-00366">Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan;<email>chlilee@mail.cmu.edu.tw</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-biomolecules-10-00366">Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40447</wicri:regionArea><wicri:noRegion>Taichung 40447</wicri:noRegion></affiliation><affiliation><nlm:aff id="af6-biomolecules-10-00366">Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Yen, Hung Rong" sort="Yen, Hung Rong" uniqKey="Yen H" first="Hung-Rong" last="Yen">Hung-Rong Yen</name><affiliation><nlm:aff id="af6-biomolecules-10-00366">Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af7-biomolecules-10-00366">Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402</wicri:regionArea><wicri:noRegion>Taichung 40402</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af8-biomolecules-10-00366">Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Chinese Medicine, China Medical University Hospital, Taichung 40447</wicri:regionArea><wicri:noRegion>Taichung 40447</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af9-biomolecules-10-00366">Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447</wicri:regionArea><wicri:noRegion>Taichung 40447</wicri:noRegion></affiliation></author><author><name sortKey="Chang, Young Sheng" sort="Chang, Young Sheng" uniqKey="Chang Y" first="Young-Sheng" last="Chang">Young-Sheng Chang</name><affiliation><nlm:aff id="af2-biomolecules-10-00366">Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Lin, Yu Ping" sort="Lin, Yu Ping" uniqKey="Lin Y" first="Yu-Ping" last="Lin">Yu-Ping Lin</name><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Huang, Su Hua" sort="Huang, Su Hua" uniqKey="Huang S" first="Su-Hua" last="Huang">Su-Hua Huang</name><affiliation><nlm:aff id="af10-biomolecules-10-00366">Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan;<email>shhuang@asia.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Lin, Cheng Wen" sort="Lin, Cheng Wen" uniqKey="Lin C" first="Cheng-Wen" last="Lin">Cheng-Wen Lin</name><affiliation><nlm:aff id="af1-biomolecules-10-00366">PhD Program for Health Science and Industry, College of Health Care, China Medical University, Taichung 40402, Taiwan;<email>chijoan0805@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-10-00366">Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af6-biomolecules-10-00366">Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af10-biomolecules-10-00366">Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan;<email>shhuang@asia.edu.tw</email></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32120929</idno><idno type="pmc">7175275</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175275</idno><idno type="RBID">PMC:7175275</idno><idno type="doi">10.3390/biom10030366</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000613</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000613</idno><idno type="wicri:Area/Pmc/Curation">000613</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000613</idno><idno type="wicri:Area/Pmc/Checkpoint">000647</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000647</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Antiviral Action of Tryptanthrin Isolated from <italic>Strobilanthes cusia</italic> Leaf against Human Coronavirus NL63</title><author><name sortKey="Tsai, Yu Chi" sort="Tsai, Yu Chi" uniqKey="Tsai Y" first="Yu-Chi" last="Tsai">Yu-Chi Tsai</name><affiliation><nlm:aff id="af1-biomolecules-10-00366">PhD Program for Health Science and Industry, College of Health Care, China Medical University, Taichung 40402, Taiwan;<email>chijoan0805@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-10-00366">Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Lee, Chia Lin" sort="Lee, Chia Lin" uniqKey="Lee C" first="Chia-Lin" last="Lee">Chia-Lin Lee</name><affiliation><nlm:aff id="af4-biomolecules-10-00366">Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan;<email>chlilee@mail.cmu.edu.tw</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-biomolecules-10-00366">Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40447</wicri:regionArea><wicri:noRegion>Taichung 40447</wicri:noRegion></affiliation><affiliation><nlm:aff id="af6-biomolecules-10-00366">Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Yen, Hung Rong" sort="Yen, Hung Rong" uniqKey="Yen H" first="Hung-Rong" last="Yen">Hung-Rong Yen</name><affiliation><nlm:aff id="af6-biomolecules-10-00366">Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af7-biomolecules-10-00366">Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402</wicri:regionArea><wicri:noRegion>Taichung 40402</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af8-biomolecules-10-00366">Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Department of Chinese Medicine, China Medical University Hospital, Taichung 40447</wicri:regionArea><wicri:noRegion>Taichung 40447</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="af9-biomolecules-10-00366">Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan</nlm:aff><country xml:lang="fr">Taïwan</country><wicri:regionArea>Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447</wicri:regionArea><wicri:noRegion>Taichung 40447</wicri:noRegion></affiliation></author><author><name sortKey="Chang, Young Sheng" sort="Chang, Young Sheng" uniqKey="Chang Y" first="Young-Sheng" last="Chang">Young-Sheng Chang</name><affiliation><nlm:aff id="af2-biomolecules-10-00366">Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Lin, Yu Ping" sort="Lin, Yu Ping" uniqKey="Lin Y" first="Yu-Ping" last="Lin">Yu-Ping Lin</name><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Huang, Su Hua" sort="Huang, Su Hua" uniqKey="Huang S" first="Su-Hua" last="Huang">Su-Hua Huang</name><affiliation><nlm:aff id="af10-biomolecules-10-00366">Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan;<email>shhuang@asia.edu.tw</email></nlm:aff></affiliation></author><author><name sortKey="Lin, Cheng Wen" sort="Lin, Cheng Wen" uniqKey="Lin C" first="Cheng-Wen" last="Lin">Cheng-Wen Lin</name><affiliation><nlm:aff id="af1-biomolecules-10-00366">PhD Program for Health Science and Industry, College of Health Care, China Medical University, Taichung 40402, Taiwan;<email>chijoan0805@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af2-biomolecules-10-00366">Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af3-biomolecules-10-00366">Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af6-biomolecules-10-00366">Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></nlm:aff></affiliation><affiliation><nlm:aff id="af10-biomolecules-10-00366">Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan;<email>shhuang@asia.edu.tw</email></nlm:aff></affiliation></author></analytic><series><title level="j">Biomolecules</title><idno type="eISSN">2218-273X</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><italic>Strobilanthes cusia</italic> (Nees) Kuntze is a Chinese herbal medicine used in the treatment of respiratory virus infections. The methanol extract of <italic>S. cusia</italic> leaf contains chemical components such as β-sitosterol, indirubin, tryptanthrin, betulin, indigodole A, and indigodole B that have diverse biological activities. However, the antiviral action of <italic>S. cusia</italic> leaf and its components against human coronavirus remains to be elucidated. Human coronavirus NL63 infection is frequent among immunocompromised individuals, young children, and in the elderly. This study investigated the anti-Human coronavirus NL63 (HCoV-NL63) activity of the methanol extract of <italic>S. cusia</italic> leaf and its major components. The methanol extract of <italic>S. cusia</italic> leaf effectively inhibited the cytopathic effect (CPE) and virus yield (IC<sub>50</sub> = 0.64 μg/mL) in HCoV-NL63-infected cells. Moreover, this extract potently inhibited the HCoV-NL63 infection in a concentration-dependent manner. Among the six components identified in the methanol extract of <italic>S. cusia</italic> leaf, tryptanthrin and indigodole B (5a<italic>R</italic>-ethyltryptanthrin) exhibited potent antiviral activity in reducing the CPE and progeny virus production. The IC<sub>50</sub> values against virus yield were 1.52 μM and 2.60 μM for tryptanthrin and indigodole B, respectively. Different modes of time-of-addition/removal assay indicated that tryptanthrin prevented the early and late stages of HCoV-NL63 replication, particularly by blocking viral RNA genome synthesis and papain-like protease 2 activity. Notably, tryptanthrin (IC<sub>50</sub> = 0.06 μM) and indigodole B (IC<sub>50</sub> = 2.09 μM) exhibited strong virucidal activity as well. This study identified tryptanthrin as the key active component of <italic>S. cusia</italic> leaf methanol extract that acted against HCoV-NL63 in a cell-type independent manner. The results specify that tryptanthrin possesses antiviral potential against HCoV-NL63 infection.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lin, W" uniqKey="Lin W">W. Lin</name></author><author><name sortKey="Huang, W" uniqKey="Huang W">W. Huang</name></author><author><name sortKey="Ning, S" uniqKey="Ning S">S. Ning</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author><author><name sortKey="Ye, Q" uniqKey="Ye Q">Q. Ye</name></author><author><name sortKey="Wei, D" uniqKey="Wei D">D. Wei</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, H" uniqKey="Chen H">H. Chen</name></author><author><name sortKey="Shao, J" uniqKey="Shao J">J. Shao</name></author><author><name sortKey="Zhang, H" uniqKey="Zhang H">H. Zhang</name></author><author><name sortKey="Jiang, M" uniqKey="Jiang M">M. Jiang</name></author><author><name sortKey="Huang, L" uniqKey="Huang L">L. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Biomolecules</journal-id><journal-id journal-id-type="iso-abbrev">Biomolecules</journal-id><journal-id journal-id-type="publisher-id">biomolecules</journal-id><journal-title-group><journal-title>Biomolecules</journal-title></journal-title-group><issn pub-type="epub">2218-273X</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32120929</article-id><article-id pub-id-type="pmc">7175275</article-id><article-id pub-id-type="doi">10.3390/biom10030366</article-id><article-id pub-id-type="publisher-id">biomolecules-10-00366</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Antiviral Action of Tryptanthrin Isolated from <italic>Strobilanthes cusia</italic> Leaf against Human Coronavirus NL63</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tsai</surname><given-names>Yu-Chi</given-names></name><xref ref-type="aff" rid="af1-biomolecules-10-00366">1</xref><xref ref-type="aff" rid="af2-biomolecules-10-00366">2</xref><xref ref-type="aff" rid="af3-biomolecules-10-00366">3</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-5949-1989</contrib-id><name><surname>Lee</surname><given-names>Chia-Lin</given-names></name><xref ref-type="aff" rid="af4-biomolecules-10-00366">4</xref><xref ref-type="aff" rid="af5-biomolecules-10-00366">5</xref><xref ref-type="aff" rid="af6-biomolecules-10-00366">6</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0131-1658</contrib-id><name><surname>Yen</surname><given-names>Hung-Rong</given-names></name><xref ref-type="aff" rid="af6-biomolecules-10-00366">6</xref><xref ref-type="aff" rid="af7-biomolecules-10-00366">7</xref><xref ref-type="aff" rid="af8-biomolecules-10-00366">8</xref><xref ref-type="aff" rid="af9-biomolecules-10-00366">9</xref></contrib><contrib contrib-type="author"><name><surname>Chang</surname><given-names>Young-Sheng</given-names></name><xref ref-type="aff" rid="af2-biomolecules-10-00366">2</xref><xref ref-type="aff" rid="af3-biomolecules-10-00366">3</xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Yu-Ping</given-names></name><xref ref-type="aff" rid="af3-biomolecules-10-00366">3</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Su-Hua</given-names></name><xref ref-type="aff" rid="af10-biomolecules-10-00366">10</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-0165-2652</contrib-id><name><surname>Lin</surname><given-names>Cheng-Wen</given-names></name><xref ref-type="aff" rid="af1-biomolecules-10-00366">1</xref><xref ref-type="aff" rid="af2-biomolecules-10-00366">2</xref><xref ref-type="aff" rid="af3-biomolecules-10-00366">3</xref><xref ref-type="aff" rid="af6-biomolecules-10-00366">6</xref><xref ref-type="aff" rid="af10-biomolecules-10-00366">10</xref><xref rid="c1-biomolecules-10-00366" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-biomolecules-10-00366"><label>1</label>PhD Program for Health Science and Industry, College of Health Care, China Medical University, Taichung 40402, Taiwan;<email>chijoan0805@gmail.com</email></aff><aff id="af2-biomolecules-10-00366"><label>2</label>Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan;<email>a0989016192@gmail.com</email></aff><aff id="af3-biomolecules-10-00366"><label>3</label>Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan;<email>c20234@hotmail.com</email></aff><aff id="af4-biomolecules-10-00366"><label>4</label>Department of Cosmeceutics, China Medical University, Taichung 40402, Taiwan;<email>chlilee@mail.cmu.edu.tw</email></aff><aff id="af5-biomolecules-10-00366"><label>5</label>Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan</aff><aff id="af6-biomolecules-10-00366"><label>6</label>Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan;<email>hungrongyen@gmail.com</email></aff><aff id="af7-biomolecules-10-00366"><label>7</label>Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan</aff><aff id="af8-biomolecules-10-00366"><label>8</label>Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan</aff><aff id="af9-biomolecules-10-00366"><label>9</label>Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan</aff><aff id="af10-biomolecules-10-00366"><label>10</label>Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan;<email>shhuang@asia.edu.tw</email></aff><author-notes><corresp id="c1-biomolecules-10-00366"><label>*</label>Correspondence: <email>cwlin@mail.cmu.edu.tw</email>; Fax: 886-4-2205-7414</corresp></author-notes><pub-date pub-type="epub"><day>27</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>3</month><year>2020</year></pub-date><volume>10</volume><issue>3</issue><elocation-id>366</elocation-id><history><date date-type="received"><day>19</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>25</day><month>2</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p><italic>Strobilanthes cusia</italic> (Nees) Kuntze is a Chinese herbal medicine used in the treatment of respiratory virus infections. The methanol extract of <italic>S. cusia</italic> leaf contains chemical components such as β-sitosterol, indirubin, tryptanthrin, betulin, indigodole A, and indigodole B that have diverse biological activities. However, the antiviral action of <italic>S. cusia</italic> leaf and its components against human coronavirus remains to be elucidated. Human coronavirus NL63 infection is frequent among immunocompromised individuals, young children, and in the elderly. This study investigated the anti-Human coronavirus NL63 (HCoV-NL63) activity of the methanol extract of <italic>S. cusia</italic> leaf and its major components. The methanol extract of <italic>S. cusia</italic> leaf effectively inhibited the cytopathic effect (CPE) and virus yield (IC<sub>50</sub> = 0.64 μg/mL) in HCoV-NL63-infected cells. Moreover, this extract potently inhibited the HCoV-NL63 infection in a concentration-dependent manner. Among the six components identified in the methanol extract of <italic>S. cusia</italic> leaf, tryptanthrin and indigodole B (5a<italic>R</italic>-ethyltryptanthrin) exhibited potent antiviral activity in reducing the CPE and progeny virus production. The IC<sub>50</sub> values against virus yield were 1.52 μM and 2.60 μM for tryptanthrin and indigodole B, respectively. Different modes of time-of-addition/removal assay indicated that tryptanthrin prevented the early and late stages of HCoV-NL63 replication, particularly by blocking viral RNA genome synthesis and papain-like protease 2 activity. Notably, tryptanthrin (IC<sub>50</sub> = 0.06 μM) and indigodole B (IC<sub>50</sub> = 2.09 μM) exhibited strong virucidal activity as well. This study identified tryptanthrin as the key active component of <italic>S. cusia</italic> leaf methanol extract that acted against HCoV-NL63 in a cell-type independent manner. The results specify that tryptanthrin possesses antiviral potential against HCoV-NL63 infection.</p></abstract><kwd-group><kwd><italic>Strobilanthes cusia</italic></kwd><kwd>tryptanthrin</kwd><kwd>indigodole B</kwd><kwd>human coronavirus NL63</kwd><kwd>antiviral</kwd><kwd>virucidal</kwd></kwd-group></article-meta></front><floats-group><fig id="biomolecules-10-00366-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Inhibitory effects of <italic>S. cusia</italic> leaf methanol extract on viral cytopathicity and progeny virus production in HCoV-NL63-infected cells. LLC-MK-2 cells were infected with HCoV-NL63 at 0.01 multiplicity of infection (MOI) and simultaneously treated with the extract. Virus-induced cytopathic effects were imaged 36 h post-infection (hpi) by microscopy (<bold>A</bold>). The supernatant from treated infected cells was harvested 36 hpi and serially diluted for determining the HCoV-NL63 yield in the supernatant using the plaque assay (<bold>B</bold>, right y axis). The rate of virus yield inhibition was calculated based on the ratio of the loss in the titer of the treated group to mock-treated group (<bold>B</bold>, left y axis). +, add; −, not add; *, <italic>p</italic> value < 0.05; ***, <italic>p</italic> value < 0.001 compared with mock-treated infected cells. Scale bar, 100 μM.</p></caption><graphic xlink:href="biomolecules-10-00366-g001"></graphic></fig><fig id="biomolecules-10-00366-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Inhibition of HCoV-NL63 infectivity by <italic>S. cusia</italic> leaf methanol extract. LLC-MK2 cells were infected with HCoV-NL63 and immediately treated with the extract for 36 h at 37 °C, and then subjected to immunofluorescence staining with anti-HCoV-NL63 immunized sera and secondary antibody Alexa Fluor anti-mouse IgG (<bold>A</bold>, top); total cells were stained with 4′,6-diamidino-2-phenylindole (DAPI) (<bold>A</bold>, bottom). Infectivity inhibition was determined according to the decrease in the ratio of HCoV-NL63-positive cells to total cells (<bold>B</bold>). +, add; −, not add; ***, <italic>p</italic> value < 0.001 compared with untreated infected cells. Scale bar, 100 μM.</p></caption><graphic xlink:href="biomolecules-10-00366-g002"></graphic></fig><fig id="biomolecules-10-00366-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Inhibitory effects of <italic>S. cusia</italic> extract components on viral cytopathicity and HCoV-NL63 infectivity. LLC-MK2 cells were infected with HCoV-NL63 and immediately treated with 40 μM of the indicated components for 36 h at 37 °C, photographed for evaluating the relative cytopathic effect (CPE) levels (<bold>A</bold>), and the residual HCoV-NL63 infectivity was determined using immunofluorescence staining with anti-HCoV-NL63 antibodies (<bold>B</bold>, top) and DAPI (<bold>B</bold>, bottom). The ratio of HCoV-NL63-positive cells was calculated as the percentage of positive cells to total cells (<bold>C</bold>). +, add; −, not add; ***, <italic>p</italic> value < 0.001 compared with mock-treatment group. Scale bar, 100 μM.</p></caption><graphic xlink:href="biomolecules-10-00366-g003"></graphic></fig><fig id="biomolecules-10-00366-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Inhibition of viral cytopathicity and virus yield by tryptanthrin and indigodole B. The structure of tryptanthrin and indigodole B is shown in (<bold>A</bold>). Images of CPE reduction by tryptanthrin and indigodole B were captured 36 hpi (<bold>B</bold>,<bold>C</bold>). The inhibitory activity of tryptanthrin and indigodole B on virus yield was calculated based on the ratio of titer loss in the treated group to that in the mock-treated group (<bold>D</bold>,<bold>E</bold>). +, add; −, not add; **, <italic>p</italic> value < 0.01; ***, <italic>p</italic> value < 0.001 compared with untreated infected cells. Scale bar, 100 μM.</p></caption><graphic xlink:href="biomolecules-10-00366-g004"></graphic></fig><fig id="biomolecules-10-00366-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Tryptanthrin inhibited HCoV-NL63 infectivity in human airway epithelial cells. Calu-3 cells were infected with HCoV-NL63 and immediately treated with tryptanthrin for 36 h at 32 °C. Images of relative CPE levels in each group were captured (<bold>A</bold>, top). In addition, the cells were subjected to immunofluorescence staining with anti-HCoV-NL63 antibodies plus secondary antibody Alexa Fluor anti-mouse IgG (<bold>A</bold>, middle) and DAPI (<bold>A</bold>, bottom). Infectivity inhibition activity was determined based on the change in the percentage of HCoV-NL63-positive cells (<bold>B</bold>). +, add; −, not add; **, <italic>p</italic> value < 0.01; ***, <italic>p</italic> value < 0.001 compared with untreated infected group. Scale bar, 100 μM.</p></caption><graphic xlink:href="biomolecules-10-00366-g005"></graphic></fig><fig id="biomolecules-10-00366-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Time-of-addition and removal assay for analyzing antiviral action of tryptanthrin against HCoV-NL63. The cell monolayer was infected with HCoV-NL63 and treated with tryptanthrin simultaneously (<bold>A</bold>, early stage), or 1 hpi (<bold>C</bold>, late stage). After a 2 h of incubation, the virus/tryptanthrin mixture was removed; the cell monolayer was washed with PBS and cultured for an additional 36 h with incubation at 37 °<italic>C</italic>, and then subjected to immunofluorescence staining using anti-HCoV-NL63 antibodies plus secondary antibody Alexa Fluor anti-mouse IgG (<bold>A</bold>,<bold>C</bold>, top) and DAPI (<bold>A</bold>,<bold>C</bold>, bottom). Infectivity was determined according to the percentage of HCoV-NL63-positive cells (<bold>B</bold>,<bold>D</bold>). +, add;−, not add; ***, <italic>p</italic> value < 0.001 compared with untreated infected group. Scale bar, 100 μM.</p></caption><graphic xlink:href="biomolecules-10-00366-g006"></graphic></fig><fig id="biomolecules-10-00366-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>Time-of-addition and removal assay for examining the effect of tryptanthrin on the early and late stages of HCoV-NL63 replication. The cell monolayer was infected with HCoV-NL63 and treated with tryptanthrin simultaneously (<bold>A</bold>, early stage), or 1 hpi (<bold>B</bold>, late stage). After 2 h of incubation, the virus/tryptanthrin mixture was removed; the cell monolayer was washed with PBS and cultured for an additional 36 h with incubation at 37 °C. The extracellular virus yield in the supernatant was determined using the plaque assay; the inhibition rate was analyzed based on the loss in the ratio of virus titer in treated group to that in the mock-treated group. **, <italic>p</italic> value < 0.01; ***, <italic>p</italic> value < 0.001 compared with mock-treated infected cells.</p></caption><graphic xlink:href="biomolecules-10-00366-g007"></graphic></fig><fig id="biomolecules-10-00366-f008" orientation="portrait" position="float"><label>Figure 8</label><caption><p>Inhibitory effect of tryptanthrin on the synthesis of viral RNA genome in the early and late stages of HCoV-NL63 replication. The cell monolayer was infected with HCoV-NL63 and treated with tryptanthrin simultaneously (<bold>A</bold>, early stage), or 1 hpi (<bold>B</bold>, late stage). After 2 h of incubation, the virus/tryptanthrin mixture was removed; the cell monolayer was washed with PBS and cultured for an additional 24 h with incubation at 37 <italic>°</italic>C. Total RNA from treated and transfected cells was extracted and reverse transcribed with HCoV-NL63-specific primers. Relative viral RNA genomes were measured by quantitative PCR and normalized by β-actin mRNA. **, <italic>p</italic> value < 0.01; ***, <italic>p</italic> value < 0.001 compared with mock-treated infected cells.</p></caption><graphic xlink:href="biomolecules-10-00366-g008"></graphic></fig><fig id="biomolecules-10-00366-f009" orientation="portrait" position="float"><label>Figure 9</label><caption><p>Inhibition of in vitro <italic>trans</italic>-cleavage activity of recombinant HCoV-NL63 papain-like protease 2 by tryptanthrin. The purified recombinant HCoV-NL63 papain-like protease 2 (PLP2) was analyzed by 10% SDS-PAGE with Coomassie blue staining (<bold>A</bold>, right) and Western Blotting with anti-His tag antibodies (<bold>A</bold>, left). The <italic>trans</italic>-cleavage activity of HCoV-NL63 PLP2 was evaluated using the ELISA with horseradish peroxidase (HRP) containing an LXGG motif as the substrate. After 2 h of incubation at 37 °C, the enzyme activity of the residual HRP (in intact form) was detected using a chromogen reagent (ABTS/H<sub>2</sub>O<sub>2</sub>). The ELISA product was measured at A<sub>405 nm</sub> (<bold>B</bold>). Tryptanthrin at indicated concentrations was added into the mixture of HCoV-NL63 PLP2 and HRP, and then incubated for 2 h at 37 °C. Lastly, the enzyme activity of the residual HRP (in intact form) was determined using the chromogen reagent (ABTS/H<sub>2</sub>O<sub>2</sub>), calculated as 1−(OD405 with PLP2)/(OD405 without PLP2) (<bold>C</bold>). Moreover, the relative inhibition of the cleavage activity of PLP2 by tryptanthrin was estimated as 1−(OD405 without PLP2−OD405 with PLP2 plus tryptanthrin)/(OD405 without PLP2−OD405 with PLP2) (<bold>D</bold>). **, <italic>p</italic> value < 0.01; ***, <italic>p</italic> value < 0.001 compared with the mock-treated group.</p></caption><graphic xlink:href="biomolecules-10-00366-g009"></graphic></fig><fig id="biomolecules-10-00366-f010" orientation="portrait" position="float"><label>Figure 10</label><caption><p>Virucidal activity of tryptanthrin, indigodole B, and <italic>S. cusia</italic> extract. Tryptanthrin (<bold>A</bold>), indigodole B (<bold>B</bold>), or the extract (<bold>C</bold>) at the indicated concentrations was mixed with HCoV-NL63 (10<sup>5</sup> pfu), and incubated at 37 <italic>°</italic>C for 1 h. The 1000-fold dilution of the compound/virus mixture was added into the LLC<italic>-</italic>MK2 cell monolayer in 6-well plates for examining the residual infectivity by plaque assay. Virucidal activity was calculated based on the percentage of residual plaques in each treated group. ***, <italic>p</italic> value < 0.001 compared with untreated infected cells.</p></caption><graphic xlink:href="biomolecules-10-00366-g010"></graphic></fig><fig id="biomolecules-10-00366-f011" orientation="portrait" position="float"><label>Figure 11</label><caption><p>Dot-blotting assay of the HCoV-NL63/tryptanthrin mixture incubated at 37 <italic>°</italic>C for 1 h. Tryptanthrin at indicated concentrations was mixed with HCoV-NL63 (10<sup>5</sup> pfu), and then incubated <italic>at 37 °</italic>C for 1 h. Fifteen microliters of the compound/virus mixture was added onto the nitrocellulose membrane. The nitrocellulose membrane was blocked with 5% skim milk in Tris-Buffered Saline plus 0.1% Tween-20 (TBST) for 2 h, incubated with anti-HCoV-NL63 antibodies overnight, and then reacted with HRP-conjugated anti-mouse IgG antibodies. After washing with TBST, immunoreactive spots of HCoV-NL63 were developed with ECLTM Western Blotting Detection Reagents, and then imaged by the Multi-function Gel Image System. +, add; −, not add;</p></caption><graphic xlink:href="biomolecules-10-00366-g011"></graphic></fig><table-wrap id="biomolecules-10-00366-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">biomolecules-10-00366-t001_Table 1</object-id><label>Table 1</label><caption><p>Cytotoxicity and anti-human coronavirus NL63 (HCoV-NL63) activity of <italic>Strobilanthes cusia</italic> leaf methanol extract, indigodole B, and tryptantrin.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Tests</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"><italic>S. cusia</italic> Extract<break></break>(μg/mL)<sup>a</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Indigodole B<break></break>(μM)<sup>a</sup></th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Tryptanthrin<break></break>(μM)<sup>a</sup></th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1"><bold>LCC-MK2 cells at 37 °C</bold></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Cytotoxicity (CC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1">> 100 </td><td align="center" valign="middle" rowspan="1" colspan="1">> 4 00</td><td align="center" valign="middle" rowspan="1" colspan="1">> 400</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Virus yield inhibition using plaque assay (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.64 ± 0.43</td><td align="center" valign="middle" rowspan="1" colspan="1">2.60 ± 0.11</td><td align="center" valign="middle" rowspan="1" colspan="1">1.52 ± 0.13</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Virucidal activity using plaque assay</td><td align="center" valign="middle" rowspan="1" colspan="1">0.12 ± 0.03</td><td align="center" valign="middle" rowspan="1" colspan="1">2.09 ± 0.89</td><td align="center" valign="middle" rowspan="1" colspan="1">0.06 ± 0.04</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Infectivity inhibition with the compound in 0.01 N HCl (pH 2.0) for 15 min using IFA<sup>b</sup> (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">0.67 ± 0.03</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Infectivity inhibition with the compound in 0.01 N HCl (pH 2.0) for 60 min using IFA (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">1.58 ± 0.15</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Infectivity inhibition at the early stage using IFA (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">0.32 ± 0.05</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Infectivity inhibition at the late stage using IFA (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">0.06 ± 0.03</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Production inhibition of extracellular virions at the early stage using plaque assay (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">6.99 ± 2.18</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Production inhibition of extracellular virions at the late stage using plaque assay (IC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">0.05 ± 0.03</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Calu-3 cells at 32 °C</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Cytotoxicity (CC<sub>50</sub>)</td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">72.5 ± 0.77</td><td align="center" valign="middle" rowspan="1" colspan="1">173.2 ± 1.3</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Infectivity inhibition using IFA (IC<sub>50</sub>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.30 ± 0.01</td></tr></tbody></table><table-wrap-foot><fn><p><sup>a</sup> Mean ± standard deviation. <sup>b</sup> Immunofluorescence assay. </p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Taïwan</li></country></list><tree><noCountry><name sortKey="Chang, Young Sheng" sort="Chang, Young Sheng" uniqKey="Chang Y" first="Young-Sheng" last="Chang">Young-Sheng Chang</name><name sortKey="Huang, Su Hua" sort="Huang, Su Hua" uniqKey="Huang S" first="Su-Hua" last="Huang">Su-Hua Huang</name><name sortKey="Lin, Cheng Wen" sort="Lin, Cheng Wen" uniqKey="Lin C" first="Cheng-Wen" last="Lin">Cheng-Wen Lin</name><name sortKey="Lin, Yu Ping" sort="Lin, Yu Ping" uniqKey="Lin Y" first="Yu-Ping" last="Lin">Yu-Ping Lin</name><name sortKey="Tsai, Yu Chi" sort="Tsai, Yu Chi" uniqKey="Tsai Y" first="Yu-Chi" last="Tsai">Yu-Chi Tsai</name></noCountry><country name="Taïwan"><noRegion><name sortKey="Lee, Chia Lin" sort="Lee, Chia Lin" uniqKey="Lee C" first="Chia-Lin" last="Lee">Chia-Lin Lee</name></noRegion><name sortKey="Yen, Hung Rong" sort="Yen, Hung Rong" uniqKey="Yen H" first="Hung-Rong" last="Yen">Hung-Rong Yen</name><name sortKey="Yen, Hung Rong" sort="Yen, Hung Rong" uniqKey="Yen H" first="Hung-Rong" last="Yen">Hung-Rong Yen</name><name sortKey="Yen, Hung Rong" sort="Yen, Hung Rong" uniqKey="Yen H" first="Hung-Rong" last="Yen">Hung-Rong Yen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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