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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late
Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory
Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome
Coronavirus (SARS-CoV)<xref ref-type="fn" rid="FN1">*</xref></title><author><name sortKey="Zhou, Nan" sort="Zhou, Nan" uniqKey="Zhou N" first="Nan" last="Zhou">Nan Zhou</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Pan, Ting" sort="Pan, Ting" uniqKey="Pan T" first="Ting" last="Pan">Ting Pan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Zhang, Junsong" sort="Zhang, Junsong" uniqKey="Zhang J" first="Junsong" last="Zhang">Junsong Zhang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Li, Qianwen" sort="Li, Qianwen" uniqKey="Li Q" first="Qianwen" last="Li">Qianwen Li</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Zhang, Xue" sort="Zhang, Xue" uniqKey="Zhang X" first="Xue" last="Zhang">Xue Zhang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Bai, Chuan" sort="Bai, Chuan" uniqKey="Bai C" first="Chuan" last="Bai">Chuan Bai</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Huang, Feng" sort="Huang, Feng" uniqKey="Huang F" first="Feng" last="Huang">Feng Huang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Peng, Tao" sort="Peng, Tao" uniqKey="Peng T" first="Tao" last="Peng">Tao Peng</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Jianhua" sort="Zhang, Jianhua" uniqKey="Zhang J" first="Jianhua" last="Zhang">Jianhua Zhang</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Liu, Chao" sort="Liu, Chao" uniqKey="Liu C" first="Chao" last="Liu">Chao Liu</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Tao, Liang" sort="Tao, Liang" uniqKey="Tao L" first="Liang" last="Tao">Liang Tao</name><affiliation><nlm:aff id="aff2">Department of Pharmacology, Zhongshan School of Medicine,</nlm:aff></affiliation></author><author><name sortKey="Zhang, Hui" sort="Zhang, Hui" uniqKey="Zhang H" first="Hui" last="Zhang">Hui Zhang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26953343</idno><idno type="pmc">4861487</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861487</idno><idno type="RBID">PMC:4861487</idno><idno type="doi">10.1074/jbc.M116.716100</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000D81</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D81</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late
Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory
Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome
Coronavirus (SARS-CoV)<xref ref-type="fn" rid="FN1">*</xref></title><author><name sortKey="Zhou, Nan" sort="Zhou, Nan" uniqKey="Zhou N" first="Nan" last="Zhou">Nan Zhou</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Pan, Ting" sort="Pan, Ting" uniqKey="Pan T" first="Ting" last="Pan">Ting Pan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Zhang, Junsong" sort="Zhang, Junsong" uniqKey="Zhang J" first="Junsong" last="Zhang">Junsong Zhang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Li, Qianwen" sort="Li, Qianwen" uniqKey="Li Q" first="Qianwen" last="Li">Qianwen Li</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Zhang, Xue" sort="Zhang, Xue" uniqKey="Zhang X" first="Xue" last="Zhang">Xue Zhang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Bai, Chuan" sort="Bai, Chuan" uniqKey="Bai C" first="Chuan" last="Bai">Chuan Bai</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Huang, Feng" sort="Huang, Feng" uniqKey="Huang F" first="Feng" last="Huang">Feng Huang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Peng, Tao" sort="Peng, Tao" uniqKey="Peng T" first="Tao" last="Peng">Tao Peng</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Zhang, Jianhua" sort="Zhang, Jianhua" uniqKey="Zhang J" first="Jianhua" last="Zhang">Jianhua Zhang</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Liu, Chao" sort="Liu, Chao" uniqKey="Liu C" first="Chao" last="Liu">Chao Liu</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author><author><name sortKey="Tao, Liang" sort="Tao, Liang" uniqKey="Tao L" first="Liang" last="Tao">Liang Tao</name><affiliation><nlm:aff id="aff2">Department of Pharmacology, Zhongshan School of Medicine,</nlm:aff></affiliation></author><author><name sortKey="Zhang, Hui" sort="Zhang, Hui" uniqKey="Zhang H" first="Hui" last="Zhang">Hui Zhang</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff3">Key Laboratory of Tropical Disease Control of Ministry of Education</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Ebola virus infection can cause severe hemorrhagic fever with a high mortality in
humans. The outbreaks of Ebola viruses in 2014 represented the most serious
Ebola epidemics in history and greatly threatened public health worldwide. The
development of additional effective anti-Ebola therapeutic agents is therefore
quite urgent. In this study, via high throughput screening of Food and Drug
Administration-approved drugs, we identified that teicoplanin, a glycopeptide
antibiotic, potently prevents the entry of Ebola envelope pseudotyped viruses
into the cytoplasm. Furthermore, teicoplanin also has an inhibitory effect on
transcription- and replication-competent virus-like particles, with an
IC<sub>50</sub> as low as 330 n<sc>m</sc>. Comparative analysis further
demonstrated that teicoplanin is able to block the entry of Middle East
respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS)
envelope pseudotyped viruses as well. Teicoplanin derivatives such as
dalbavancin, oritavancin, and telavancin can also inhibit the entry of Ebola,
MERS, and SARS viruses. Mechanistic studies showed that teicoplanin blocks Ebola
virus entry by specifically inhibiting the activity of cathepsin L, opening a
novel avenue for the development of additional glycopeptides as potential
inhibitors of cathepsin L-dependent viruses. Notably, given that teicoplanin has
routinely been used in the clinic with low toxicity, our work provides a
promising prospect for the prophylaxis and treatment of Ebola, MERS, and SARS
virus infection.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Kiley, M X0a P" uniqKey="Kiley M">M.
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biol Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Biol. Chem</journal-id><journal-id journal-id-type="hwp">jbc</journal-id><journal-id journal-id-type="pmc">jbc</journal-id><journal-id journal-id-type="publisher-id">JBC</journal-id><journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0021-9258</issn><issn pub-type="epub">1083-351X</issn><publisher><publisher-name>American Society for Biochemistry and Molecular
Biology</publisher-name><publisher-loc>11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110,
U.S.A.</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26953343</article-id><article-id pub-id-type="pmc">4861487</article-id><article-id pub-id-type="publisher-id">M116.716100</article-id><article-id pub-id-type="doi">10.1074/jbc.M116.716100</article-id><article-categories><subj-group subj-group-type="heading"><subject>Microbiology</subject></subj-group></article-categories><title-group><article-title>Glycopeptide Antibiotics Potently Inhibit Cathepsin L in the Late
Endosome/Lysosome and Block the Entry of Ebola Virus, Middle East Respiratory
Syndrome Coronavirus (MERS-CoV), and Severe Acute Respiratory Syndrome
Coronavirus (SARS-CoV)<xref ref-type="fn" rid="FN1">*</xref></article-title><alt-title alt-title-type="short">Glycopeptide Antibiotics Inhibit Virus
Entry</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Nan</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref><xref ref-type="author-notes" rid="FN2"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pan</surname><given-names>Ting</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref><xref ref-type="author-notes" rid="FN2"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Junsong</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Qianwen</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Xue</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bai</surname><given-names>Chuan</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Feng</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peng</surname><given-names>Tao</given-names></name><xref ref-type="aff" rid="aff5"><sup>‖</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Jianhua</given-names></name><xref ref-type="aff" rid="aff6">**</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Chao</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tao</surname><given-names>Liang</given-names></name><xref ref-type="aff" rid="aff2"><sup>‡‡</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Hui</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="aff" rid="aff3"><sup>§</sup></xref><xref ref-type="aff" rid="aff4"><sup>¶</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1">From the<label>‡</label>Institute of Human Virology,</aff><aff id="aff2"><label>‡‡</label>Department of Pharmacology, Zhongshan School of Medicine,</aff><aff id="aff3"><label>§</label>Key Laboratory of Tropical Disease Control of Ministry of Education, and</aff><aff id="aff4"><label>¶</label>Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Sun Yat-sen University, Guangzhou 510080, Guangdong,</aff><aff id="aff5">the<label>‖</label>Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou 510182, Guangdong, and</aff><aff id="aff6">the<label>**</label>CAS Key Laboratory for Pathogenic Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China</aff></contrib-group><author-notes><corresp id="cor1"><label>2</label> To whom correspondence should be addressed.
Tel.: <phone>86-20-87332588</phone>; Fax: <fax>86-20-87332588</fax>; E-mail:
<email>zhangh92@mail.sysu.edu.cn</email>.</corresp><fn fn-type="equal" id="FN2"><label>1</label><p>Both authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>22</day><month>4</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>7</day><month>3</month><year>2016</year></pub-date><volume>291</volume><issue>17</issue><fpage>9218</fpage><lpage>9232</lpage><history><date date-type="received"><day>16</day><month>1</month><year>2016</year></date><date date-type="rev-recd"><day>3</day><month>3</month><year>2016</year></date></history><permissions><copyright-statement>© 2016 by The American Society for Biochemistry and
Molecular Biology, Inc.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>The American Society for Biochemistry and Molecular Biology,
Inc.</copyright-holder><license><license-p>This article is made available via the PMC Open Access Subset for
unrestricted re-use and analyses in any form or by any means with
acknowledgement of the original source. These permissions are granted for
the duration of the COVID-19 pandemic or until permissions are revoked in
writing. Upon expiration of these permissions, PMC is granted a perpetual
license to make this article available via PMC and Europe PMC, consistent
with existing copyright protections.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="zbc01716009218.pdf"></self-uri><abstract><p>Ebola virus infection can cause severe hemorrhagic fever with a high mortality in
humans. The outbreaks of Ebola viruses in 2014 represented the most serious
Ebola epidemics in history and greatly threatened public health worldwide. The
development of additional effective anti-Ebola therapeutic agents is therefore
quite urgent. In this study, via high throughput screening of Food and Drug
Administration-approved drugs, we identified that teicoplanin, a glycopeptide
antibiotic, potently prevents the entry of Ebola envelope pseudotyped viruses
into the cytoplasm. Furthermore, teicoplanin also has an inhibitory effect on
transcription- and replication-competent virus-like particles, with an
IC<sub>50</sub> as low as 330 n<sc>m</sc>. Comparative analysis further
demonstrated that teicoplanin is able to block the entry of Middle East
respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS)
envelope pseudotyped viruses as well. Teicoplanin derivatives such as
dalbavancin, oritavancin, and telavancin can also inhibit the entry of Ebola,
MERS, and SARS viruses. Mechanistic studies showed that teicoplanin blocks Ebola
virus entry by specifically inhibiting the activity of cathepsin L, opening a
novel avenue for the development of additional glycopeptides as potential
inhibitors of cathepsin L-dependent viruses. Notably, given that teicoplanin has
routinely been used in the clinic with low toxicity, our work provides a
promising prospect for the prophylaxis and treatment of Ebola, MERS, and SARS
virus infection.</p></abstract><kwd-group><kwd>antibiotics</kwd><kwd>Ebola virus</kwd><kwd>glycoprotein</kwd><kwd>lysosome</kwd><kwd>virus entry</kwd><kwd>MERS-CoV</kwd><kwd>SARS-CoV</kwd><kwd>glycopeptide</kwd></kwd-group></article-meta></front><body><sec sec-type="intro"><title>Introduction</title><p>Ebola virus (EBOV)<xref ref-type="fn" rid="FN3"><sup>3</sup></xref> is a
filamentous-enveloped, single-stranded, and negative-sense RNA virus, which is
taxonomically classified to the Filoviridae (<xref rid="B1" ref-type="bibr">1</xref>). To date, five species in the <italic>Ebolavirus</italic> genus have been
identified, including <italic>Zaire</italic>, <italic>Sudan</italic>,
<italic>Reston</italic>, <italic>Tai Forest</italic>, and <italic>Bundibugyo
ebolavirus</italic> (<xref rid="B2" ref-type="bibr">2</xref><xref ref-type="bibr" rid="B3">–</xref><xref rid="B6" ref-type="bibr">6</xref>). Ebola virus infection leads to severe viral hemorrhagic fever in
humans and non-human primates. In March 2014, outbreaks of Ebola viruses began in
Guinea and caused over 28,000 cases of infection and over 11,000 deaths, which posed
a severe threat to public health worldwide.</p><p>The Ebola virus genome contains seven genes that encode the NP, VP35, VP40,
glycoprotein (GP), VP30, VP24, and RNA-dependent RNA polymerase (L) virus proteins.
To infect host cells, the GPs of Ebola viruses first bind to attachment molecules
such as β1 integrins, DC-SIGNs, L-SIGNs, lectins, TIM-1s, Tyro3 family
proteins, heparan sulfates, or folate receptor-α (<xref rid="B7" ref-type="bibr">7</xref><xref ref-type="bibr" rid="B8">–</xref><xref rid="B13" ref-type="bibr">13</xref>). Ebola viruses are
then internalized by macropinocytosis and subsequently transported through the early
and late endosomes and the endo/lysosomes (<xref rid="B14" ref-type="bibr">14</xref><xref ref-type="bibr" rid="B15">–</xref><xref rid="B16" ref-type="bibr">16</xref>), where the Ebola virus GPs are cleaved by cathepsin L and
subsequently cathepsin B to expose the receptor-binding domains (<xref rid="B17" ref-type="bibr">17</xref>). After binding the specific receptor NPC1,
Ebola viruses release their genomes into the cytoplasm of the host cells (<xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B18" ref-type="bibr">18</xref>).</p><p>Anti-EBOV vaccines and drugs are under extensive development. Two promising vaccines,
rVSVΔG-EBOV-GP and cAd3-EBOV, have been shown to render non-human primates
resistant to Ebola virus infections and are currently in clinical trials (<xref rid="B19" ref-type="bibr">19</xref>, <xref rid="B20" ref-type="bibr">20</xref>).
In addition, the anti-EBOV monoclonal antibody Zmapp, siRNAs, and other compounds
that can inhibit Ebola virus infections have been developed (<xref rid="B21" ref-type="bibr">21</xref><xref ref-type="bibr" rid="B22">–</xref><xref rid="B24" ref-type="bibr">24</xref>). Furthermore, several clinically approved
drugs were also reported to inhibit Ebola virus infections (<xref rid="B25" ref-type="bibr">25</xref>, <xref rid="B26" ref-type="bibr">26</xref>). However,
because the IC<sub>50</sub> values of those drugs were relatively high, more
anti-EBOV drugs with potent inhibitory activity are urgently needed. To facilitate
their identification, the method of high throughput screening of clinically approved
drugs, which could be applied immediately in the clinic, is a reasonable approach.
In this study, we identified teicoplanin and several other glycopeptide antibiotics
as Ebola virus entry inhibitors with high efficiency and low cytotoxicity, providing
a promising means to effect the prophylaxis and treatment of Ebola virus
infection.</p></sec><sec sec-type="methods"><title>Experimental Procedures</title><sec><title></title><sec><title></title><sec><title>Cell Culture</title><p>HEK293T, A549, HeLa, Huh7.5.1, and Madin-Darby canine kidney cell lines
were maintained in Dulbecco's modified Eagle's medium (Gibco) with 10%
fetal calf serum (Gibco), 100 units/ml penicillin, and 100 μg/ml
streptomycin (Gibco) at 37 °C and 5% CO<sub>2</sub>. THP-1 cell
lines were maintained in RPMI1640 medium (Gibco) with 10% fetal calf
serum, 100 units/ml penicillin, and 100 μg/ml streptomycin at 37
°C and 5% CO<sub>2</sub>. Primary human umbilical vein endothelial
cells were maintained in human endothelial-SFM (Gibco) with 30 ng/ml
endothelial cell growth supplement (Merck Millipore), 20 ng/ml
recombinant human FGF basic (146 amino acids) protein (R&D Systems),
20% fetal calf serum, 100 units/ml penicillin, and 100 μg/ml
streptomycin at 37 °C and 5% CO<sub>2</sub>.</p></sec><sec><title>Plasmids</title><p>GP sequence of Zaire EBOV-2014 was chemically synthesized and inserted
into pcDNA3.1 plasmid. The pHIV-luciferase and pCMV-VSV-G plasmids were
obtained from Addgene, and the pCMV-ΔR8.2 plasmid was kindly
provided by Dr. Trono (<xref rid="B27" ref-type="bibr">27</xref>). The
p4cis plasmid that encodes a <italic>Renilla</italic> luciferase
reporter, VP40, GP and VP24, the pCAGGS-NP, pCAGGS-VP35, pCAGGS-VP30,
pCAGGS-L, pCAGGS-T7, and pCAGGS-Tim1 plasmids were produced as described
previously (<xref rid="B28" ref-type="bibr">28</xref>).</p></sec><sec><title>Viruses</title><p>Pseudotyped viruses were produced by the co-transfection of
pHIV-luciferase, pCMV-ΔR8.2, and different envelope plasmids into
HEK293T cells that were 90% confluent in a 10-cm plate with
Lipofectamine 2000 by following the manufacturer's instructions
(Invitrogen). The amounts of plasmids were listed as follows:
HIV-luc/Zaire EBOV-GP(2014) pseudotyped viruses: 4.5 μg of
pHIV-luciferase, 4.5 μg of pCMV-ΔR8.2, and 7.65 μg of
pcDNA3.1-Zaire EBOV-GP(2014); HIV-luc/VSV-G pseudotyped viruses: 4.5
μg of pHIV-luciferase, 4.5 μg of pCMV-ΔR8.2, and 2.7
μg of pCMV-VSV-G; HIV-luc/SARS-CoV-S pseudotyped viruses: 6.5
μg of pHIV-luciferase, 8 μg of pCMV-ΔR8.2, and 20
μg of pcDNA3.1-SARS-CoV-S; and HIV-luc/MERS-CoV-S pseudotyped
viruses: 4.5 μg of pHIV-luciferase, 4.5 μg of
pCMV-ΔR8.2, and 10 μg of pcDNA3.1-MERS-CoV-S. After 48 h,
the supernatants that contain the pseudotyped viruses were collected and
filtered through a 0.45-μm pore-size filter (Pall) and then stored
at −80 °C until use. Ebola transcription- and
replication-competent virus-like particles (trVLPs) were produced by the
co-transfection of 250 ng of p4cis plasmids that encode a
<italic>Renilla</italic> luciferase reporter gene, VP40, GP, and
VP24, 250 ng of pCAGGS-T7, 125 ng of pCAGGS-NP, 125 ng of pCAGGS-VP35,
75 ng of pCAGGS-VP30, and 1000 ng of pCAGGS-L plasmids into HEK293T
cells that were 50% confluent in a 6-well plate with Lipofectamine 2000
(Invitrogen). After 24 h, the medium was discarded, and the cells were
incubated with fresh medium for 48 h. Then the supernatants that contain
Ebola transcription- and replication-competent virus-like particles were
collected and filtered through a 0.45-μm pore-size filter (Pall)
and stored at −80 °C until use.</p></sec><sec><title>High Throughput Screening of FDA-approved Drug Library</title><p>High throughput screening of FDA-approved drug library (Topscience) was
conducted in 96-well plates with 50 μ<sc>m</sc> compounds per
well. HEK293T cells were incubated with compounds at 37 °C for 1 h
and then infected with 100 μl of p24-normalized (5 ng)
HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses containing 10
μg/ml Polybrene. After 12 h, the medium was discarded, and the
cells were washed briefly with PBS and incubated with fresh medium for
48 h. The intracellular luciferase activity was examined with
GloMax® 96 Microplate luminometer (Promega), and the compounds that
have the effects of more than 50% inhibition on the luciferase activity
were selected for the secondary screening, which was executed with both
HIV-luc/Zaire EBOV-GP (2014) and HIV-luc/VSV-G pseudotyped viruses in a
similar procedure.</p></sec><sec><title>Cell Viability Assay</title><p>HEK293T cells were seeded in a 96-well plate (2 × 10<sup>4</sup> per
well). After 24 h, the cells were incubated with teicoplanin at
different concentrations at 37 °C for 48 h. The cell viability then
was determined by the CellTiter® 96 Aqueous One Solution Cell
Proliferation Assay (Promega).</p></sec><sec><title>Time-of-Addition Assay</title><p>HEK293T cells were seeded in a 96-well plate (2 × 10<sup>4</sup> per
well). Twenty four hours later, the cells were infected with
HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses and incubated with 50
μ<sc>m</sc> teicoplanin at 0, 2, 4, or 8 h post-infection.
After 12 h, the medium was discarded, and the cells were washed briefly
with PBS and incubated with fresh medium for 48 h. Then the
intracellular luciferase activity was determined. The HIV-luc/VSV-G
pseudotyped viruses were used as the controls for specificity.</p></sec><sec><title>Virion Entry or Uptake Assay</title><p>HEK293T cells were seeded in a 6-well plate (2 × 10<sup>5</sup> per
well). After 24 h, the cells were incubated with teicoplanin at various
concentrations at 37 °C for 1 h and then infected with
p24-normalized (100 ng) HIV-luc/Zaire EBOV-GP (2014) or HIV-luc/VSV-G
pseudotyped viruses per well. For virion entry assay, after 6 h, the
cells were washed twice with PBS and incubated with 0.25% trypsin at 37
°C for 2 min to remove the viruses that adhered to the cell
surfaces. The cells were then collected and lysed, and the intracellular
amount of HIV-1 p24 was then measured by ELISA. For virion uptake assay,
after 0.5, 1, or 2 h, the cells were washed twice with PBS and incubated
with 0.25% trypsin at 37 °C for 2 min to remove the viruses that
adhered to the cell surfaces. The cells were then collected and lysed,
and the intracellular amount of HIV-1 p24 was then measured by
ELISA.</p></sec><sec><title>Viral Entry Inhibition on Various Cell Types</title><p>Primary human umbilical vein endothelial cells, A549 cells, and HeLa
cells were seeded in a 96-well plate (2 × 10<sup>4</sup> per well).
After 24 h, the cells were incubated with teicoplanin at various
concentrations at 37 °C for 1 h. The cells were then infected with
HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses. After 12 h, the medium
was discarded, and the cells were washed briefly with PBS and incubated
with fresh medium for 48 h. Then the intracellular luciferase activity
was measured. The THP-1 cells were plated in a 48-well format (1.25
× 10<sup>5</sup> per well) and incubated with teicoplanin at
various concentrations at 37 °C for 1 h. The cells were then
infected with HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses. After 12
h, the supernatants were removed by centrifugation at 300 ×
<italic>g</italic> for 10 min, and the cells were suspended and
cultured with RPMI 1640 medium at 37 °C for 48 h. The intracellular
luciferase activity was determined. HEK293T cells were seeded in a
96-well plate (2 × 10<sup>4</sup> per well). After 24 h, the cells
were incubated with teicoplanin at gradient concentrations at 37 °C
for 1 h. The cells were then infected with HIV-luc/SARS-CoV-S or
HIV-luc/MERS-CoV-S pseudotyped viruses. After 12 h, the medium was
discarded, and the cells were washed briefly with PBS and incubated with
fresh medium for 48 h. The intracellular luciferase activity was then
measured. For the Ebola trVLPs entry inhibition assay, HEK293T cells
were seeded in a 96-well plate (2 × 10<sup>4</sup> per well). After
24 h, in the pre-transfection experiment, the cells were pre-transfected
with 12.5 ng of pCAGGS-NP, 12.5 ng of pCAGGS-VP35, 7.5 ng of
pCAGGS-VP30, 100 ng of pCAGGS-L, 25 ng of pCAGGS-T7, and 25 ng of
pCAGGS-Tim1 plasmids with Lipofectamine 2000 according to the supplier's
protocol (Invitrogen). After 24 h, the medium was discarded, and the
cells were incubated with teicoplanin with the gradient concentrations
at 37 °C for 1 h. In the non-pre-transfection experiment, HEK293T
cells were directly incubated with teicoplanin with the gradient
concentrations at 37 °C for 1 h without the pre-transfections of
the above plasmids. The cells were then infected with Ebola trVLPs.
After 12 h, the medium was discarded, and the cells were washed briefly
with PBS and incubated with fresh medium for 48 h. Then the
intracellular luciferase activity was measured.</p></sec><sec><title>Compound/Virus or Compound/Cell Pre-incubation Assay</title><p>p24-normalized (50 ng) HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses
were incubated with 50 μ<sc>m</sc> teicoplanin in a 96-well plate
at 37 °C for 12 h. Then the compound/virus mixtures were
transferred into a Microcon 30-kDa centrifugal filter device (Millipore)
and centrifuged (7000 × <italic>g</italic>) at 4 °C for 15
min. Afterward the fresh medium was twice added onto the filter device
to wash the compound/virus mixtures. Then 0.5 ml of DMEM was used to
suspend the compound/virus mixtures, and the filter device was
centrifuged in reverse (500 × <italic>g</italic>) at 4 °C for
5 min, and the solution was collected and used to infect HEK293T cells
after HIV-1 p24 normalization. After 48 h, the intracellular luciferase
activity was measured. For compound/cell pre-treatment assays, HEK293T
cells were seeded in a 96-well plate (2 × 10<sup>4</sup> per well).
After 24 h, the cells were incubated with teicoplanin at various
concentrations at 37 °C for 12 h. The medium was discarded, and the
cells were twice washed with PBS and incubated with fresh medium.
Afterward the cells were infected with HIV-luc/Zaire EBOV-GP (2014)
pseudotyped viruses. Twelve hours later, the medium was discarded, and
the cells were washed briefly with PBS and incubated with fresh medium
for 48 h. The intracellular luciferase activity was then measured.</p></sec><sec><title>siRNA Transfection, RNA Isolation, Reverse Transcription, and
Quantitative Real Time-PCR</title><p>HEK293T cells were seeded in a 96-well plate (1 × 10<sup>4</sup> per
well). After 24 h, the cells were transfected with siRNAs at a final
concentration of 200 n<sc>m</sc> via Lipofectamine® RNAiMAX
according to the supplier's protocol (Invitrogen). Forty eight hours
later, the cells were lysed by TRIzol® reagent (Invitrogen), and
the isolation of total RNAs was conducted according to the supplier's
protocol (Invitrogen). The RNAs were reverse-transcripted by PrimeScript
RT reagent kit (TaKaRa), and the quantitative RT-PCRs were conducted on
a Bio-Rad CFX96 real time-PCR detection system (Bio-Rad) with SYBR
Premix Ex Taq (TaKaRa). After the initial denaturation of cDNA was
performed at 95 °C for 5 min, 40 cycles of the procedures (10 s of
denaturation at 95 °C, 30 s of annealing at 60 °C, and 30 s of
extension at 72 °C) were performed with the primers for human
<italic>GAPDH</italic>, <italic>ACTB</italic>, and a variety of
target genes. The smart pools of siRNAs were obtained from RIBOBIO.</p></sec><sec><title>Dextran Uptake Assay and Immunofluorescence Assay</title><p>The procedures previously described were followed with minor
modifications (<xref rid="B29" ref-type="bibr">29</xref>). Briefly,
HEK293T cells were incubated with 50 μ<sc>m</sc> teicoplanin for
12 h. Then the cells were incubated with 1 mg/ml dextran-Alexa Fluor 568
(<italic>M</italic><sub>r</sub> 10,000) (Thermo Fisher Scientific)
for 2 h in 1% serum-containing DMEM. The cells were washed twice with
PBS and incubated with 4% polyformaldehyde at room temperature for 10
min. The cells were washed twice with PBS and incubated with 0.1% Triton
X-100 at room temperature for 10 min, followed by incubation with PBS
containing 5% bovine serum albumin at room temperature for 1 h.
Afterward the cells were washed with PBS and incubated with rabbit
anti-LAMP1 antibodies (Proteintech) at room temperature for 1 h. The
cells were washed with PBS containing 0.1% Tween 20 three times and
incubated with DyLight®488-conjugated goat anti-rabbit IgG (Abcam)
at room temperature for 45 min, followed by washing with PBS containing
0.1% Tween 20 three times, and incubated with 5 μg/ml DAPI at room
temperature for 5 min. The cells were then washed again with PBS
containing 0.1% Tween 20 three times. Images were obtained by Zeiss
LSM780 confocal microscopy using Zeiss ZFN software, and the
co-localization of dextran and LAMP1 was analyzed from 20 fields
(≥5 cells per field) per independent experiment.</p></sec><sec><title>Cathepsin L Enzymatic Inhibition Assay</title><p>Two protocols previously described were followed with minor modifications
(<xref rid="B30" ref-type="bibr">30</xref>, <xref rid="B31" ref-type="bibr">31</xref>). Briefly, HEK293T cells were seeded in a black
96-well plate. After 24 h, the cells were incubated with teicoplanin or
Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl ketones, cathepsin L
inhibitor III (Millipore) at various concentrations at 37 °C for 4
h. Then the cells were washed with PBS and incubated with 100 μl
of PBS containing 50 μ<sc>m</sc> (Z-Phe-Arg)<sub>2</sub>-R110 per
well at 37 °C for 90 min. Afterward the fluorescence was tested by
a fluorometer with excitation at 488 nm and emission at 510 nm. For
<italic>in vitro</italic> enzymatic assay, 20 μl of 2
μ<sc>m</sc> recombinant human cathepsin L (rhCTSL) (Sino
Biological Inc) and 60 μl of buffer (400 m<sc>m</sc> NaOAc, 4
m<sc>m</sc> EDTA, pH 5.5) containing teicoplanin or
Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl ketones were incubated
at 37 °C for 4 h. Then the rhCTSL/compound mixtures were incubated
further with 20 μl of 50 μ<sc>m</sc>(Z-Phe-Arg)<sub>2</sub>-R110. After 4 h, the fluorescence was tested by
a fluorometer with excitation at 488 nm and emission at 510 nm.</p></sec></sec></sec></sec><sec sec-type="results"><title>Results</title><sec><title></title><sec><title></title><sec><title>High Throughput Screening of Ebola Virus Entry Inhibitors</title><p>We initiated our screening procedure by generating HIV-luc/Zaire EBOV-GP
(2014) pseudotyped viruses. The viruses were allowed to infect HEK293T
cells in the presence of a 1600-member FDA-approved drug library.
Compounds that inhibited virus luciferase activity were identified as
the initial hits. As shown in <xref rid="T1" ref-type="table">Table
1</xref>, we identified 133 hits that could inhibit the entry of
HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses. To exclude the hits
that only inhibited early events of the HIV-1 life cycle and to identify
EBOV-GP-specific drugs, HIV-luc/VSV-G pseudotyped viruses bearing
vesicular stomatitis virus (VSV) glycoproteins were used for secondary
screening of the initial hit compounds. Finally, two drugs that act
specifically as Ebola virus entry inhibitors were identified,
teicoplanin and amiodarone (<xref ref-type="fig" rid="F1">Fig.
1</xref><italic>A</italic>).</p><table-wrap id="T1" orientation="portrait" position="float"><label>TABLE 1</label><caption><p><bold>The results of the high throughput screening of the
clinically approved drug library</bold></p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="center" rowspan="1" colspan="1">Parameter</th><th align="center" rowspan="1" colspan="1">No.</th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1">Clinically approved
drugs screened</td><td align="left" rowspan="1" colspan="1">1600</td></tr><tr><td align="left" rowspan="1" colspan="1">Clinically approved
drugs that inhibit the entrances of HIV-luc/Zaire
EBOV-GP(2014) pseudotype viruses<xref ref-type="table-fn" rid="TF1-1"><italic><sup>a</sup></italic></xref></td><td align="left" rowspan="1" colspan="1">133</td></tr><tr><td align="left" rowspan="1" colspan="1">Clinically approved
drugs that inhibit the entrances of HIV-luc/VSV-G
pseudotype viruses</td><td align="left" rowspan="1" colspan="1">131</td></tr><tr><td align="left" rowspan="1" colspan="1">Clinically approved
drugs that specifically inhibit the entrances of
HIV-luc/Zaire EBOV-GP(2014) pseudotype viruses</td><td align="left" rowspan="1" colspan="1">2</td></tr></tbody></table><table-wrap-foot><fn id="TF1-1"><p><italic><sup>a</sup></italic> To deal with the threats of the
outbreaks of Ebola viral infection in 2014, the
pcDNA3.1-Zaire EBOV-GP (2014) plasmids encoding the Zaire
Ebola virus glycoproteins were synthesized and transfected
into HEK293T cells with pHIV-luciferase plasmids and
pCMV-ΔR8.2 plasmids to produce HIV-luc/Zaire EBOV-GP
(2014) pseudotype viruses.</p></fn></table-wrap-foot></table-wrap><fig id="F1" orientation="portrait" position="float"><label>FIGURE 1.</label><caption><p><bold>Teicoplanin specifically inhibits the entry of Ebola
viruses.</bold><italic>A</italic>, teicoplanin and amiodarone specifically
inhibit the entry of Ebola viruses. HEK293T cells were seeded in
a 96-well plate, and 24 h later, the cells were incubated with
various reagents at 37 °C for 1 h. The cells were then
infected with HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses.
After washing and incubation with fresh medium for 48 h, the
intracellular luciferase activity was measured.
<italic>B</italic>, chemical structure of teicoplanin.
<italic>C</italic>, HEK293T cells were incubated with
teicoplanin at various concentrations at 37 °C for 1 h. The
intracellular luciferase activity was measured at 48 h
post-infection. The IC<sub>50</sub> was calculated using
GraphPad Prism software. <italic>D</italic>, HEK293T cells were
incubated with 500 μ<sc>m</sc> teicoplanin at 37 °C
for 48 h. Then the cell viability was determined.
<italic>E</italic>, HEK293T cells were infected with
HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses and incubated
with 50 μ<sc>m</sc> teicoplanin at 0, 2, 4, and 8 h
post-infection. The cells were then incubated for 48 h after
which the intracellular luciferase activity was tested. The
HIV-luc/VSV-G pseudotyped viruses were used as the controls for
specificity. <italic>F</italic>, HEK293T cells were seeded in a
6-well plate (2 × 10<sup>5</sup> per well). After 24 h, the
cells were incubated with teicoplanin at various concentrations
at 37 °C for 1 h and then infected with p24-normalized (100
ng) HIV-luc/Zaire EBOV-GP (2014) or HIV-luc/VSV-G pseudotyped
viruses per well. After 6 h, the cells were washed with PBS
twice and incubated with 0.25% trypsin at 37 °C for 2 min
to remove the viruses that adhered to the cell surfaces. The
cells were then collected and lysed, and the intracellular
amount of HIV-1 p24 was measured by ELISA. The results are
representatives of at least three independent experiments. The
<italic>bars</italic> show the mean values ± S.D.
(<italic>error bars</italic>). The <italic>p</italic> value
was determined by a Student's <italic>t</italic> test. ***,
<italic>p</italic> < 0.001.</p></caption><graphic xlink:href="zbc0201642750001"></graphic></fig></sec><sec><title>Teicoplanin Specifically Inhibits the Entry of Ebola Viruses</title><p>Teicoplanin is a glycopeptide antibiotic that includes five major
components based on different side chains (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>B</italic>). It demonstrated an
IC<sub>50</sub> of 0.34 μ<sc>m</sc> for its inhibitory effect
on HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>C</italic>). The
cytotoxicity of teicoplanin was also determined using a cell viability
assay, and its <italic>CC</italic><sub>50</sub> was greater than 500
μ<sc>m</sc> (<xref ref-type="fig" rid="F1">Fig.
1</xref><italic>D</italic>). To further confirm whether teicoplanin
acts as an Ebola virus entry inhibitor, a time-of-addition assay was
conducted. The data showed that teicoplanin represses the entry of Ebola
viruses at the early stage of Ebola virus infection (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>E</italic>). In
addition, a virion entry assay also demonstrated that teicoplanin
inhibits the entry of HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses
in a dose-dependent manner. However, teicoplanin does not repress the
entry of HIV-luc/VSV-G pseudotyped viruses (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>F</italic>).</p><p>Ebola viruses can infect a wide range of host cells, including vascular
endothelial cells, epithelial cells, and monocytes, which account for
the pathogenesis observed in Ebola-infected patients (<xref rid="B32" ref-type="bibr">32</xref>, <xref rid="B33" ref-type="bibr">33</xref>). Thus, it was important to examine whether teicoplanin
could repress the entry of Ebola viruses into different types of cells.
The data showed that teicoplanin effectively represses virus entry into
primary human umbilical vein endothelial cells (<xref ref-type="fig" rid="F2">Fig. 2</xref><italic>A</italic>), human epithelial cell
lines such as A549 (<xref ref-type="fig" rid="F2">Fig.
2</xref><italic>B</italic>) and HeLa cells (<xref ref-type="fig" rid="F2">Fig. 2</xref><italic>C</italic>), and the human acute
monocytic leukemia THP-1 cell line (<xref ref-type="fig" rid="F2">Fig.
2</xref><italic>D</italic>).</p><fig id="F2" orientation="portrait" position="float"><label>FIGURE 2.</label><caption><p><bold>Ebola virus entry into different cell types is repressed by
teicoplanin.</bold><italic>A</italic>, primary human umbilical vein endothelial
cells were seeded in a 96-well plate. After 24 h, the cells were
incubated with teicoplanin at various concentrations at 37
°C for 1 h. Subsequently, the cells were infected with
HIV-luc/Zaire EBOV-GP (2014) pseudotyped viruses. After washing
and incubation with fresh medium for 48 h, the intracellular
luciferase activity was measured. <italic>B</italic>, antiviral
entry assay of teicoplanin on the A549 cells was conducted in a
similar way. <italic>C</italic>, antiviral entry assay of
teicoplanin on the HeLa cells was conducted in a similar
procedure. <italic>D</italic>, THP-1 cells were incubated with
teicoplanin at various concentrations at 37 °C for 1 h.
Subsequently, the cells were infected with HIV-luc/Zaire EBOV-GP
(2014) pseudotyped viruses. After 12 h, the supernatants were
removed by centrifugation at 300 × <italic>g</italic> for
10 min, and the cells were suspended and cultured with RPMI 1640
medium at 37 °C for 48 h. The intracellular luciferase
activity was then tested. The results are representative of at
least three independent experiments. The <italic>bars</italic>show the mean values ± S.D. (<italic>error bars</italic>).
The <italic>p</italic> value was determined by a Student's
<italic>t</italic> test. **, <italic>p</italic> < 0.01;
***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="zbc0201642750002"></graphic></fig></sec><sec><title>Teicoplanin Targets the Host Cells Rather than the Cell-free Viral
Particles</title><p>To elucidate the molecular mechanisms of the anti-Ebola virus activity of
teicoplanin, it is necessary to determine whether the target of
teicoplanin is located directly on the virus itself. The compound virus
pre-incubation assay demonstrated that when teicoplanin was
pre-incubated with Ebola/HIV pseudotyped viruses and then filtered and
washed away, the inhibitory effect of the antibiotic on Ebola virus
entry did not occur (<xref ref-type="fig" rid="F3">Fig.
3</xref><italic>A</italic>). However, the compound cell
pre-treatment assay showed that when the host cells were pre-treated
with teicoplanin and subsequently washed to remove the drug, its
inhibitory effect on Ebola/HIV pseudotyped viruses remained (<xref ref-type="fig" rid="F3">Fig. 3</xref><italic>B</italic>). Together,
these data indicated that the target of teicoplanin is located on the
host cells.</p><fig id="F3" orientation="portrait" position="float"><label>FIGURE 3.</label><caption><p><bold>Target of teicoplanin is located within the host
cells.</bold><italic>A</italic>, p24-normalized (50 ng) HIV-luc/Zaire EBOV-GP
(2014) pseudotyped viruses were incubated with 50
μ<sc>m</sc> teicoplanin in a 96-well plate at 37
°C for 12 h. Then the compound virus mixtures were
transferred into a Microcon 30-kDa centrifugal filter device
(Millipore) and centrifuged (7000 × <italic>g</italic>) at
4 °C for 15 min. Subsequently, fresh medium was added twice
onto the filter device to wash the compound virus mixtures. Then
0.5 ml of DMEM was used to suspend the compound virus mixtures,
and the reversed filter device was centrifuged (500 ×
<italic>g</italic>) at 4 °C for 5 min. The solution was
collected and used to infect HEK293T cells after HIV-1 p24
normalization. After 48 h, the intracellular luciferase activity
was measured. <italic>B</italic>, HEK293T cells were incubated
with teicoplanin at various concentrations for 12 h. The cells
were then infected with HIV-luc/Zaire EBOV-GP (2014) pseudotyped
viruses. After washing and incubation with fresh medium for 48
h, the intracellular luciferase activity was measured. The assay
during treatment was the same as the antiviral entry assay. The
results are representative of at least three independent
experiments. The <italic>bars</italic> show the mean values
± S.D. (<italic>error bars</italic>). The
<italic>p</italic> value was determined by a Student's
<italic>t</italic> test. <italic>n.s.</italic>, not
significant; **, <italic>p</italic> < 0.01; ***,
<italic>p</italic> < 0.001.</p></caption><graphic xlink:href="zbc0201642750003"></graphic></fig></sec><sec><title>Teicoplanin Does Not Block Cell Receptors</title><p>To clarify the molecular mechanism of teicoplanin action, we tested
whether teicoplanin inhibits the entry of other viruses able to utilize
similar intracellular transport routes as those employed by Ebola
viruses. It has been reported that both Ebola viruses and SARS
coronaviruses (SARS-CoVs) need to be transported to the endo/lysosomes
to release their genomes (<xref ref-type="fig" rid="F4">Fig.
4</xref><italic>A</italic>) (<xref rid="B18" ref-type="bibr">18</xref>). Therefore, HIV-luc/SARS-CoV-S pseudotyped viruses that
bear the S proteins of SARS-CoVs were generated and used to test whether
their entry could be repressed by teicoplanin. The data indicated that
teicoplanin also inhibits the entry of SARS-CoVs (<xref ref-type="fig" rid="F4">Fig. 4</xref><italic>B</italic>). Given that Niemann-Pick
C1 (NPC1) and angiotensin-converting enzyme 2 (ACE2) represent the cell
receptors of Ebola viruses and SARS-CoVs, respectively (<xref rid="B16" ref-type="bibr">16</xref>, <xref rid="B34" ref-type="bibr">34</xref>, <xref rid="B35" ref-type="bibr">35</xref>), and that
teicoplanin inhibits both of these viruses, it is necessary to clarify
whether Ebola viruses and SARS-CoVs share cell receptor affinity.
Following depletion of the expression of NPC1 and ACE2 in HEK293T cells
using siRNAs, the cells were infected with Ebola or SARS-CoV pseudotyped
viruses. The results demonstrated that the knockdown of NPC1 affected
the infectivity of Ebola but not that of SARS-CoV pseudotyped viruses,
whereas the converse was observed following ACE2 knockdown (<xref ref-type="fig" rid="F4">Fig. 4</xref><italic>C</italic>). This
indicates that these two viruses are each associated with specific
receptors and also excludes the possibility that teicoplanin inhibits
the interaction between the viruses and their cell receptors or the
events following receptor binding. Taken together, these data led us to
hypothesize that the target of teicoplanin would be the host factor(s)
which is (are) required for both Ebola and SARS-CoV infection.
Considering that interferon-inducible transmembrane proteins (IFITMs)
represent the first line of anti-viral defense of the cells, we first
examined the effect of teicoplanin on the expression of IFITMs. However,
the data showed that teicoplanin did not induce the expression of IFITMs
(data not shown).</p><fig id="F4" orientation="portrait" position="float"><label>FIGURE 4.</label><caption><p><bold>Teicoplanin does not block the cell receptor.</bold><italic>A</italic>, schematic representation of the entry of
Ebola viruses and SARS-CoVs. <italic>B</italic>, HEK293T cells
were incubated with teicoplanin at various concentrations at 37
°C for 1 h. The cells were then infected with
HIV-luc/SARS-CoV-S pseudotyped viruses. After washing and
incubation with fresh medium for 48 h, the intracellular
luciferase activity was measured. <italic>C</italic>, HEK293T
cells were seeded in a 96-well plate. After 24 h, the cells were
transfected with 200 n<sc>m</sc> siRNAs against NPC1 and ACE2,
respectively. After 48 h, the cells were infected with
HIV-luc/Zaire EBOV-GP (2014) or HIV-luc/SARS-CoV-S pseudotyped
viruses. The results are representative of at least three
independent experiments. The <italic>bars</italic> show the mean
values ± S.D. (<italic>error bars</italic>). The
<italic>p</italic> value was determined by a Student's
<italic>t</italic> test. <italic>n.s.</italic>, not
significant; *, <italic>p</italic> < 0.05; **,
<italic>p</italic> < 0.01; ***, <italic>p</italic> <
0.001.</p></caption><graphic xlink:href="zbc0201642750004"></graphic></fig></sec><sec><title>Teicoplanin Has No Effect on HOPS Complexes</title><p>We further examined the host factors that are required for both Ebola
viruses and SARS-CoVs but not VSVs using siRNAs. Through genome-wide
haploid genetic screening, several host factors essential for Ebola
viral infection have been identified (<xref rid="B16" ref-type="bibr">16</xref>). Accordingly, we infected cells with Ebola-, SARS-CoV-,
or VSV-pseudotyped HIV-1 viruses after siRNA-mediated knockdown of the
expression of 13 individual host factors. We found that cathepsin L
(CTSL), VPS11, VPS18, VPS33A, VPS39, and VPS41 are required for both
Ebola and SARS-CoV infection (<xref ref-type="fig" rid="F5">Fig.
5</xref><italic>B</italic>) rather than VSV infection. These results
imply that the host factors might be the targets of teicoplanin. VPS11,
VPS18, VPS33A, VPS39, and VPS41 are components of HOPS complexes, which
mediate the homotypic fusion between late endosomes and the heterotypic
fusion between late endosomes and lysosomes (<xref rid="B29" ref-type="bibr">29</xref>, <xref rid="B36" ref-type="bibr">36</xref>,
<xref rid="B37" ref-type="bibr">37</xref>). To investigate whether
teicoplanin affects the transport of Ebola viruses by inhibiting HOPS
complex function and subsequently disturbing endosome maturation and
fusion between the late endosomes and the lysosomes, a dextran uptake
assay was conducted (<xref ref-type="fig" rid="F5">Fig.
5</xref><italic>C</italic>). We found that within 2 h of uptake, the
dextran-Alexa Fluor 568 could be transported into lysosome-associated
membrane protein 1 (LAMP1)-positive lysosomes. The co-localization
coefficient of dextran and LAMP1 was influenced by siRNA knockdown of
VPS39 and VPS41, whereas teicoplanin did not exert any effect (<xref ref-type="fig" rid="F5">Fig. 5</xref><italic>D</italic>). These data
indicated that teicoplanin does not inhibit the transport of
dextran-Alexa Fluor 568. Therefore, it is unlikely that teicoplanin
inhibits the entry of Ebola viruses by affecting HOPS complexes. In
addition, we conducted virion uptake assays to demonstrate that
teicoplanin does not inhibit both Ebola- and VSV-pseudotyped virion
uptake at 0.5, 1, and 2 h post-infection (<xref ref-type="fig" rid="F5">Fig. 5</xref>, <italic>E</italic> and <italic>F</italic>). These
data indicated that teicoplanin did not affect the endocytosis of Ebola-
and VSV-pseudotyped virions, at least the early phase. In addition,
these data also indicated that, except HOPS complexes, teicoplanin has
no effect on the other host factors that are involved in the process of
virion uptake.</p><fig id="F5" orientation="portrait" position="float"><label>FIGURE 5.</label><caption><p><bold>Teicoplanin has no effect on HOPS complexes.</bold><italic>A</italic>, schematic representation of the entry of
Ebola viruses, SARS-CoVs, and VSVs. The host factors thatare
essential for the entry of Ebola viruses are illustrated.
<italic>B</italic>, HEK293T cells were transfected with 200
n<sc>m</sc> siRNAs per well. After 48 h, the cells were
infected with HIV-luc/Zaire EBOV-GP (2014), HIV-luc/SARS-CoV-S,
or HIV-luc/VSV pseudotyped viruses. After washing and incubation
with fresh medium for 48 h, the intracellular luciferase
activity was measured. <italic>C</italic>, HEK293T cells were
plated in a glass bottom dish. After 24 h, groups of cells were
incubated with 50 μ<sc>m</sc> teicoplanin or control for
12 h. Another group of cells was transfected with siRNAs against
VPS39 and VPS41 or the si-control and incubated with these
siRNAs at a final concentration of 200 n<sc>m</sc> for 48 h.
Then the cells were incubated with dextran-Alexa Flour 568
(<italic>M</italic><sub>r</sub> 10,000) for 2 h in 1%
serum-containing DMEM. Subsequently, the cells were subjected to
immunofluorescence analysis. Images were obtained using Zeiss
LSM780 confocal microscopy with Zeiss ZFN software.
<italic>Scale bar,</italic> 10 μm. <italic>D</italic>,
co-localization of dextran and LAMP1 was analyzed from 20 fields
(≥5 cells per field) per independent experiment.
Pearson's overlap coefficients were used to determine the levels
of the co-localization of dextran and LAMP1. <italic>E</italic>and <italic>F</italic>, HEK293T cells were incubated with
teicoplanin at the various indicated concentrations at 37
°C for 1 h. The cells were then infected with HIV-luc/Zaire
EBOV-GP (2014) or HIV-luc/VSV-G pseudotyped viruses,
respectively. Subsequently, the cells were incubated with 0.25%
trypsin at 37 °C for 2 min to remove the viruses that
adhered to the cell surfaces at 0.5, 1, and 2 h post-infection.
The intracellular amount of HIV-1 p24 was then measured by
ELISA. The results are representative of at least three
independent experiments. The <italic>bars</italic> show the mean
values ± S.D. (<italic>error bars</italic>). The
<italic>p</italic> value was determined by a Student's
<italic>t</italic> test. <italic>n.s.,</italic> not
significant; ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="zbc0201642750005"></graphic></fig></sec><sec><title>Teicoplanin Directly Inhibits the Enzymatic Activity of Cathepsin
L</title><p>After excluding the possibility that the machinery for vesicle transport
is involved in the inhibitory effect of teicoplanin, we assumed that the
enzymes in the late endosome/lysosome could be the target of
teicoplanin. The proteolysis of glycoprotein by cathepsin L has been
reported to be required for the membrane fusion of both Ebola viruses
and SARS-CoVs (<xref rid="B31" ref-type="bibr">31</xref>). In contract,
cathepsin B is required for Ebola virus infection but not SARS-CoV
infection (<xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B31" ref-type="bibr">31</xref>). As such, we hypothesized that
cathepsin L rather than cathepsin B could be the target for teicoplanin.
To this end, we examined whether teicoplanin can inhibit the enzymatic
activity of cathepsin L (<xref ref-type="fig" rid="F6">Fig.
6</xref><italic>A</italic>). Two assays to measure the cathepsin L
enzymatic activity were performed (<xref rid="B30" ref-type="bibr">30</xref>, <xref rid="B31" ref-type="bibr">31</xref>). We showed
that teicoplanin potently inhibits the activity of cathepsin L in a
dose-dependent manner (<xref ref-type="fig" rid="F6">Fig. 6</xref>,
<italic>B</italic> and <italic>E</italic>). Considering that the
inhibitory dose of teicoplanin on the activity of cathepsin L is higher
than that required for Ebola virus infection inhibition, a cell
viability assay was performed to confirm that the inhibitory effect is
not due to cytotoxicity (<xref ref-type="fig" rid="F6">Fig.
6</xref><italic>C</italic>). In addition, a comparative analysis of
the inhibitory dose of teicoplanin and that of previously reported
cathepsin L inhibitors, Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl
ketones, on Ebola virus infection was conducted. We demonstrated that
both compounds can inhibit Ebola virus infection at low doses. The
IC<sub>50</sub> dose of teicoplanin required to inhibit the Ebola
entry is approximately four times more than that of
Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl ketones (<xref ref-type="fig" rid="F6">Fig. 6</xref><italic>D</italic> and <xref rid="T2" ref-type="table">Table 2</xref>). Similarly, the
IC<sub>50</sub> dose of teicoplanin required to inhibit the
enzymatic activity of cathepsin L was also approximately four times
greater (<xref ref-type="fig" rid="F6">Fig. 6</xref>, <italic>B</italic>and <italic>E</italic>, and <xref rid="T2" ref-type="table">Table
2</xref>). These data indicated that the high doses of teicoplanin
determined to be required for the inhibition of cathepsin L enzymatic
activity could be due to the relatively low sensitivity of the cathepsin
L activity assay. These data clearly demonstrate the consistency between
the inhibition of virus entry and the inhibition of cathepsin L activity
and further support our conclusion that the target molecule of
teicoplanin is cathepsin L.</p><fig id="F6" orientation="portrait" position="float"><label>FIGURE 6.</label><caption><p><bold>Teicoplanin directly inhibits the activity of cathepsin
L.</bold><italic>A</italic>, schematic representation of the cathepsin L
enzymatic inhibition assay. <italic>B</italic>, HEK293T cells
were incubated with teicoplanin or
Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl ketones and then
incubated with 50 μ<sc>m</sc> (Z-Phe-Arg)<sub>2</sub>-R110
at 37 °C for 90 min. The level of fluorescence was
determined using a fluorometer with excitation at 488 nm and
emission at 510 nm. <italic>C</italic>, HEK293T cells were
incubated with teicoplanin at various concentrations at 37
°C for 48 h. The cell viability was then determined using
the CellTiter® 96 Aqueous One Solution Cell Proliferation
Assay. <italic>D</italic>, HEK293T cells were incubated with
teicoplanin or Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl
ketones at 37 °C for 1 h. The cells were then infected with
HIV-luc/Zaire EBOV-GP (2014) or HIV-luc/VSV-G pseudotyped
viruses. After incubation for 48 h, the intracellular luciferase
activity was measured. <italic>E</italic>, recombinant human
cathepsin L (rhCTSL), teicoplanin, or
Z-Phe-Tyr(<italic>t</italic>-Bu)-diazomethyl ketones were
incubated 37 °C for 4 h. The rhCTSL-compound mixtures were
incubated with (Z-Phe-Arg)<sub>2</sub>-R110 at 37 °C for 4
h. The fluorescence was then tested using a fluorometer with
excitation at 488 nm and emission at 510 nm. The results are
representative of at least three independent experiments. The
<italic>bars</italic> show the mean values ± S.D.
(<italic>error bars</italic>). The <italic>p</italic> value
was determined by a Student's <italic>t</italic> test.
<italic>n.s.</italic>, not significant, *,
<italic>p</italic> < 0.05; **, <italic>p</italic> <
0.01; ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="zbc0201642750006"></graphic></fig><table-wrap id="T2" orientation="portrait" position="float"><label>TABLE 2</label><caption><p><bold>The IC<sub>50</sub> value of glycopeptide antibiotics on
Ebola-trVLP entry and cathepsin L activity</bold></p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th align="center" rowspan="1" colspan="1">Compound</th><th align="center" rowspan="1" colspan="1">IC<sub>50</sub>on Ebola-trVLP entry (pretreated)</th><th align="center" rowspan="1" colspan="1">IC<sub>50</sub>on CTSL activity (method 1)</th><th align="center" rowspan="1" colspan="1">IC<sub>50</sub>on CTSL activity (method 2)</th></tr></thead><tbody valign="top"><tr><td rowspan="1" colspan="1"></td><td align="center" rowspan="1" colspan="1">μ<italic><sc>m</sc></italic></td><td align="center" rowspan="1" colspan="1">μ<italic><sc>m</sc></italic></td><td align="center" rowspan="1" colspan="1">μ<italic><sc>m</sc></italic></td></tr><tr><td align="left" rowspan="1" colspan="1">Teicoplanin</td><td align="char" char="±" rowspan="1" colspan="1">0.39
± 0.12</td><td align="char" char="±" rowspan="1" colspan="1">208.0
± 59.8</td><td align="char" char="±" rowspan="1" colspan="1">425.3
± 107.8</td></tr><tr><td align="left" rowspan="1" colspan="1">Dalbavancin</td><td align="char" char="±" rowspan="1" colspan="1">1.61
± 1.26</td><td align="char" char="±" rowspan="1" colspan="1">333.7
± 110.5</td><td align="char" char="±" rowspan="1" colspan="1">503.1
± 102.8</td></tr><tr><td align="left" rowspan="1" colspan="1">Oritavancin</td><td align="char" char="±" rowspan="1" colspan="1">1.73
± 1.24</td><td align="char" char="±" rowspan="1" colspan="1">371.8
± 142.3</td><td align="char" char="±" rowspan="1" colspan="1">548.4
± 126.1</td></tr><tr><td align="left" rowspan="1" colspan="1">Telavancin</td><td align="char" char="±" rowspan="1" colspan="1">1.89
± 1.35</td><td align="char" char="±" rowspan="1" colspan="1">377.4
± 161.3</td><td align="char" char="±" rowspan="1" colspan="1">558.8
± 72.3</td></tr><tr><td align="left" rowspan="1" colspan="1">Vancomycin</td><td align="left" rowspan="1" colspan="1">>50</td><td align="left" rowspan="1" colspan="1">>2560</td><td align="left" rowspan="1" colspan="1">>2560</td></tr><tr><td align="left" rowspan="1" colspan="1">CTSL inhibitor</td><td align="char" char="±" rowspan="1" colspan="1">0.10
± 0.03</td><td align="char" char="±" rowspan="1" colspan="1">43.53
± 18.24</td><td align="char" char="±" rowspan="1" colspan="1">127.7
± 14.2</td></tr></tbody></table></table-wrap></sec><sec><title>Entry of Ebola trVLPs Is Repressed by Several Glycopeptide
Antibiotics with the Exception of Vancomycin</title><p>An Ebola trVLP system (<xref rid="B28" ref-type="bibr">28</xref>), which
can simulate the life cycle of wild-type Ebola viruses to a large
extent, was applied to investigate whether teicoplanin and its
glycopeptide antibiotic homologs dalbavancin, oritavancin, telavancin,
and vancomycin can also inhibit the entry of Ebola trVLPs. Accordingly,
the p4cis plasmid encoding <italic>Renilla</italic> luciferase, VP40,
GP, and VP24 was transfected into HEK293T cells along with plasmids
expressing T7 RNA polymerase, NP, VP35, VP30, and L viral proteins to
produce Ebola trVLPs (<xref ref-type="fig" rid="F7">Fig.
7</xref><italic>A</italic>). When the target cells were also
pre-transfected with NP, VP35, VP30, L, T7, and Tim1 plasmids, the
transcription and replication of the Ebola virus minigenome were
actively stimulated to produce infectious Ebola trVLPs. The
IC<sub>50</sub> value of teicoplanin on Ebola trVLP entry was
∼390 n<sc>m</sc> under these conditions (<xref ref-type="fig" rid="F7">Fig. 7</xref><italic>B</italic>). Additionally, when the
target cells were not pre-transfected with the above plasmids, the Ebola
viral minigenomes were only weakly transcribed and replicated with
minimal production of infectious trVLPs. The IC<sub>50</sub> of
teicoplanin on the entry of Ebola trVLPs was ∼330 n<sc>m</sc>under the non-pre-transfection conditions (<xref ref-type="fig" rid="F7">Fig. 7</xref><italic>C</italic>). In addition, we also examined
whether the homologs of teicoplanin can inhibit Ebola trVLP entry. The
data demonstrated that the IC<sub>50</sub> values of dalbavancin,
oritavancin, and telavancin on Ebola trVLP entry were ∼1.61,
1.73, and 1.89 μ<sc>m</sc>, respectively, under pre-transfection
conditions (<xref ref-type="fig" rid="F7">Fig. 7</xref>, <italic>D,
F,</italic> and <italic>H</italic>) and ∼2.77, 2.13, and 2.30
μ<sc>m</sc>, respectively, under non-pre-transfection
conditions (<xref ref-type="fig" rid="F7">Fig. 7</xref>, <italic>E,
G,</italic> and <italic>I</italic>). However, we found that
vancomycin did not inhibit Ebola trVLP entry under either condition
(<xref ref-type="fig" rid="F7">Fig. 7</xref>, <italic>J</italic> and
<italic>K</italic>). The <italic>CC</italic><sub>50</sub> values of
dalbavancin, oritavancin, telavancin, and vancomycin were also
determined (data not shown). These data indicated that these homologs
might share similar structures that are indispensable for the inhibitory
effects on Ebola trVLP entry. However, vancomycin would not be expected
to have similar structures (<xref ref-type="fig" rid="F9">Fig.
9</xref>).</p><fig id="F7" orientation="portrait" position="float"><label>FIGURE 7.</label><caption><p><bold>Entry of Ebola trVLPs is repressed by glycopeptide
antibiotics with the exception of vancomycin.</bold><italic>A</italic>, schematic representation of the EbolatrVLPs
entry assay. <italic>B</italic>, for the pre-transfection
experiment, HEK293T cells were pre-transfected with 12.5 ng of
pCAGGS-NP, 12.5 ng of pCAGGS-VP35, 7.5 ng of pCAGGS-VP30, 100 ng
of pCAGGS-L, 25 ng of pCAGGS-T7, and 25 ng of pCAGGS-Tim1
plasmids. After 24 h, the medium was discarded, and the cells
were incubated with teicoplanin at various concentrations at 37
°C for 1 h. After washing and incubation with fresh medium
for 48 h, the intracellular luciferase activity was measured.
The IC<sub>50</sub> was calculated using GraphPad Prism
software. <italic>C</italic>, for the non-pre-transfection
experiment, HEK293T cells were incubated with teicoplanin at
various concentrations at 37 °C for 1 h without
pre-transfection of the above plasmids. The methods used for
conducting Ebola trVLPs infection and measuring the
intracellular luciferase activity were the same as those
described in <italic>B. D</italic> and <italic>E</italic>,
IC<sub>50</sub> values of dalbavancin on the entry of Ebola
trVLPs were determined under pre-transfection and
non-pre-transfection conditions, respectively.
<italic>F</italic> and <italic>G</italic>, IC<sub>50</sub>values of oritavancin on the entry of Ebola trVLPs were
calculated using pre-transfection or non-pre-transfection
conditions, respectively. <italic>H</italic> and
<italic>I</italic>, IC<sub>50</sub> values of telavancin on
the entry of Ebola trVLPs were determined under pre-transfection
and non-pre-transfection conditions, respectively.
<italic>J</italic> and <italic>K</italic>, effect of
vancomycin on the entry of Ebola trVLPs was determined using
pre-transfection or non-pre-transfection conditions,
respectively. The results are representative of at least three
independent experiments. The <italic>bars</italic> show the mean
values ± S.D. (<italic>error bars</italic>). The
<italic>p</italic> value was determined by a Student's
<italic>t</italic> test. <italic>n.s.</italic>, not
significant.</p></caption><graphic xlink:href="zbc0201642750007"></graphic></fig></sec><sec><title>MERS-CoV and SARS-CoV Entry Is Also Inhibited by Glycopeptide
Antibiotics with the Exception of Vancomycin</title><p>Because our data demonstrated that teicoplanin inhibits cathepsin L
enzymatic activity and that cathepsin L is also essential for MERS-CoV
and SARS-CoV entry (<xref rid="B31" ref-type="bibr">31</xref>, <xref rid="B38" ref-type="bibr">38</xref>), we therefore hypothesized that
teicoplanin and its homologs could also inhibit the entry of MERS-CoVs
and SARS-CoVs. The data illustrated that the IC<sub>50</sub> values of
teicoplanin, dalbavancin, oritavancin, and telavancin on MERS-CoV entry
were ∼0.63, 2.99, 2.12, and 3.24 μ<sc>m</sc> respectively
(<xref ref-type="fig" rid="F8">Fig. 8</xref>,
<italic>A–D</italic>). However, vancomycin did not inhibit
the MERS-CoV entry (<xref ref-type="fig" rid="F8">Fig.
8</xref><italic>I</italic>). Additionally, the IC<sub>50</sub>values of teicoplanin, dalbavancin, oritavancin, and telavancin on the
entry of SARS-CoVs were ∼3.76, 9.64, 4.96, and 3.45
μ<sc>m</sc>, respectively (<xref ref-type="fig" rid="F8">Fig.
8</xref>, <italic>E–H</italic>). However, vancomycin did not
inhibit the entry of SARS-CoVs (<xref ref-type="fig" rid="F8">Fig.
8</xref><italic>J</italic>). These data indicated that glycopeptide
antibiotics with the exception of vancomycin exhibit broad antiviral
activity because of their inhibitory effects on cathepsin L.</p><fig id="F8" orientation="portrait" position="float"><label>FIGURE 8.</label><caption><p><bold>Entry of MERS-CoVs and SARS-CoVs is inhibited by
glycopeptide antibiotics with the exception of
vancomycin.</bold><italic>A</italic> and <italic>E</italic>, HEK293T cells were
incubated with teicoplanin at various concentrations at 37
°C for 1 h. The cells were infected with HIV-luc/MERS-CoV-S
or HIV-luc/SARS-CoV-S pseudotyped viruses. After washing and
incubation with fresh medium for 48 h, the intracellular
luciferase activity was measured. The IC<sub>50</sub> was
calculated using GraphPad Prism software. <italic>B</italic> and
<italic>F</italic>, IC<sub>50</sub> values of dalbavancin on
the entry of HIV-luc/MERS-CoV-S and HIV-luc/SARS-CoV-S
pseudotyped viruses were determined. <italic>C</italic> and
<italic>G</italic>, IC<sub>50</sub> values of oritavancin on
the entry of HIV-luc/MERS-CoV-S and HIV-luc/SARS-CoV-S
pseudotyped viruses were calculated. <italic>D</italic> and
<italic>H</italic>, IC<sub>50</sub> values of telavancin on
the entry of HIV-luc/MERS-CoV-S and HIV-luc/SARS-CoV-S
pseudotyped viruses were determined. <italic>I</italic> and
<italic>J</italic>, The effect of vancomycin on the entry of
HIV-luc/MERS-CoV-S and HIV-luc/SARS-CoV-S pseudotyped viruses
was determined. The results are representative of at least three
independent experiments. The <italic>bars</italic> show the mean
values ± S.D. (<italic>error bars</italic>). The
<italic>p</italic> value was determined by a Student's
<italic>t</italic> test. <italic>n.s.,</italic> not
significant.</p></caption><graphic xlink:href="zbc0201642750008"></graphic></fig></sec></sec></sec></sec><sec sec-type="discussion"><title>Discussion</title><p>In our study, we performed high throughput screening of a clinically approved drug
library and identified that teicoplanin not only inhibits the entry of Ebola/HIV-1
pseudotyped viruses but also of transcription- and replication-competent trVLPs. The
IC<sub>50</sub> value of teicoplanin on the entry of Ebola trVLPs is as low as
330 n<sc>m</sc>, whereas the <italic>CC</italic><sub>50</sub> of teicoplanin is over
500 μ<sc>m</sc>. In addition, teicoplanin inhibits the entry of Ebola viruses
into different types of host cells, including primary human umbilical vein
endothelial cells, A549 cells, HeLa cells, and THP-1 cells. It also inhibits the
entry of MERS-CoV/HIV-1 and SARS-CoV/HIV-1 pseudotyped viruses.</p><p>Teicoplanin is a glycopeptide antibiotic isolated from <italic>Actinoplanes
teichomyceticus.</italic> Teicoplanin contains five major components (<xref rid="B39" ref-type="bibr">39</xref>, <xref rid="B40" ref-type="bibr">40</xref>)
that can form complexes with the C-terminal
<sc>l</sc>-Lys–<sc>d</sc>-Ala–<sc>d</sc>-Ala subunits of lipid II
peptidoglycan precursors. Teicoplanin binding of lipid II inhibits their
transglycosylation and transpeptidation, leading to disturbed cell wall synthesis in
Gram-positive bacteria (<xref rid="B41" ref-type="bibr">41</xref>). Recently,
teicoplanin was reported to inhibit Ebola pseudovirus infection in cell culture,
which is consistent with our observations. Teicoplanin was also demonstrated to have
an effect on a common component used by both enveloped Ebola viruses and human
respiratory syncytial viruses but not by non-enveloped viruses (<xref rid="B26" ref-type="bibr">26</xref>). However, the mechanism by which
teicoplanin inhibits the entry of Ebola remained unresolved. To elucidate the
molecular mechanisms underlying this process, we compared the entry of Ebola viruses
and SARS-CoVs and the effect of teicoplanin thereon. Teicoplanin represses the entry
of both Ebola viruses and SARS-CoVs, which require transport to the endo/lysosomes
to deliver their genomes. Because several host factors have been reported to be
essential for Ebola and SARS-CoV virus infection, the identification of the common
host factors that are required for the entry of both Ebola viruses and SARS-CoVs
would likely be helpful to clarify the target of teicoplanin. Our data demonstrated
that CTSL, VPS11, VPS18, VPS33A, VPS39, and VPS41 are all indispensable for the
entry of both Ebola viruses and SARS-CoVs (<xref ref-type="fig" rid="F5">Fig.
5</xref><italic>B</italic>). The elucidation via a dextran uptake assay that
teicoplanin does not affect the functions of HOPS complexes suggested that the
target of teicoplanin was cathepsin L. In support of this, the results of two
cathepsin L enzymatic activity assays indicated that teicoplanin indeed inhibits the
activity of cathepsin L, which can explain why teicoplanin inhibited both the entry
of Ebola viruses and human respiratory syncytial viruses as shown in a previous
study (<xref rid="B26" ref-type="bibr">26</xref>) because cathepsin L is required
for the infection mechanism of both (<xref rid="B17" ref-type="bibr">17</xref>,
<xref rid="B42" ref-type="bibr">42</xref>). Considering that cathepsin L is also
required for the entry of MERS-CoVs, teicoplanin thus represents a broad virus entry
inhibitor. In addition, the inhibitory effects of teicoplanin and its derivatives on
HIV-1, HCV, influenza viruses, flaviviruses, FIPV, and SARS-CoVs have also been
reported (<xref rid="B43" ref-type="bibr">43</xref><xref ref-type="bibr" rid="B44">–</xref><xref rid="B49" ref-type="bibr">49</xref>), further supporting that the antiviral target for glycopeptide
antibiotics is a common host factor.</p><p>As teicoplanin can bind lipid IIs, we hypothesized that it might interact with the
enzymatic domains of cathepsin L and block their functions similar to the reported
inhibitory effect of antimicrobial peptide LL-37 on cathepsin L (<xref rid="B50" ref-type="bibr">50</xref>). The specific binding sites of teicoplanin
on cathepsin L need to be further investigated by molecular docking, amino acid
mutation, and surface plasmon resonance to confirm this hypothesis. We also examined
the effects of the teicoplanin homologs dalbavancin, oritavancin, telavancin, and
vancomycin on the entry of Ebola trVLPs, MERS-CoV/HIV-1, and SARS-CoV/HIV-1
pseudotyped viruses. The data demonstrated that dalbavancin, oritavancin, and
telavancin also inhibit the entryof MERS-CoV/HIV-1 and SARS-CoV/HIV-1 pseudotyped
viruses. However, vancomycin did not repress their infection. By comparing the
structures of these compounds, we found that all the glycopeptide antibiotics that
inhibit Ebola trVLP, MERS-CoV/HIV-1, and SARS-CoV/HIV-1 pseudotyped virus entry
contain hydrophobic groups at the amidogen domains of their aminosaccharides. These
groups might play an important role in the interactions between the glycopeptide
antibiotics and cathepsin L. In contrast, vancomycin lacks the hydrophobic groups,
which might be the reason why it does not inhibit these viral infections (<xref ref-type="fig" rid="F9">Fig. 9</xref>).</p><fig id="F9" orientation="portrait" position="float"><label>FIGURE 9.</label><caption><p><bold>Chemical structures of glycopeptide antibiotics.</bold> Teicoplanin,
dalbavancin, oritavancin, and telavancin, which inhibit the entry of Ebola
trVLPs, MERS-CoVs, and SARS-CoVs, contain key hydrophobic groups. However,
vancomycin, which does not exert antiviral activity, does not contain these
groups.</p></caption><graphic xlink:href="zbc0201642750009"></graphic></fig><p>For the treatment of Gram-positive bacterial infections in the clinic, teicoplanin
can be administered intravenously or intramuscularly once daily following an initial
loading dose, which is convenient for outpatient therapy (<xref rid="B51" ref-type="bibr">51</xref>). Compared with vancomycin, which was the first discovered
glycopeptide antibiotic, teicoplanin is better tolerated with lower nephrotoxicity
(<xref rid="B52" ref-type="bibr">52</xref>). The Summary of Product
Characteristics for teicoplanin in 2014 shows that, after the completion of the
loading dose regimens for most Gram-positive bacterial infections, the serum
concentrations of teicoplanin are at least 15 mg/liter (8.78 μ<sc>m</sc>),
which is ∼27, 14, and 2 times higher than the IC<sub>50</sub> values of
teicoplanin against the entry of Ebola viruses, MERS-CoV/HIV-1, and SARS-CoV/HIV-1
pseudotyped viruses, respectively. As the toxicity of glycopeptide antibiotics is
quite low, we propose that glycopeptide antibiotics might be used in the clinic for
Ebola/MERS-CoV/SARS-CoV infection, especially in the case of emergency requirements
during outbreaks of these severe viral infections.</p></sec><sec><title>Author Contributions</title><p>All listed authors contributed to this work and reviewed the manuscript. N. Z. and T.
Pan designed the experiments and performed most of these experiments. J. S. Z., X.
Z., F. H., T. Peng, L. T., and J. H. Z. performed the different kinds of
virus-related experiments. Q. W. L., C. B., and C. L. carried out the high
throughput screening of the Food and Drug Administration-approved drug library. N.
Z. and H. Z. contributed to the idea generation, experimental design, and manuscript
preparation and conceived the project.</p></sec></body><back><fn-group><fn fn-type="supported-by" id="FN1"><label>*</label><p>This work was supported by National Special Research Program for the Important
Infectious Diseases Grant 2013ZX10001004, Guangdong Innovative Research Team
Program Grant 2009010058, and National Natural Science Foundation of Key
Projects Grant 81590765 (to H. Z.). The authors declare that they have no
conflicts of interest with the contents of this article.</p></fn></fn-group><fn-group content-type="abbreviations"><fn id="FN3"><label>3</label><p>The abbreviations used are: <def-list><def-item><term id="G1">EBOV</term><def><p>Ebola virus</p></def></def-item><def-item><term id="G2">trVLPs</term><def><p>transcription- and replication-competent virus-like particles</p></def></def-item><def-item><term id="G3">MERS-CoV</term><def><p>Middle East respiratory syndrome coronavirus</p></def></def-item><def-item><term id="G4">SARS-CoV</term><def><p>severe acute respiratory syndrome coronavirus</p></def></def-item><def-item><term id="G5">VSV</term><def><p>vesicular stomatitis virus</p></def></def-item><def-item><term id="G6">GP</term><def><p>glycoprotein</p></def></def-item><def-item><term id="G7">rh</term><def><p>recombinant human</p></def></def-item><def-item><term id="G8">CTSL</term><def><p>cathepsin L</p></def></def-item><def-item><term id="G9">HOPS complex</term><def><p>homotypic fusion and vacuole protein-sorting complex</p></def></def-item><def-item><term id="G10">Z</term><def><p>benzyloxycarbonyl</p></def></def-item><def-item><term id="G11"><italic>t</italic>-Bu</term><def><p><italic>t</italic>-butyl</p></def></def-item><def-item><term id="G12">IFITM</term><def><p>interferon-inducible transmembrane protein</p></def></def-item><def-item><term id="G13">FDA</term><def><p>Food and Drug Administration.</p></def></def-item></def-list></p></fn></fn-group><ack><title>Acknowledgments</title><p>We thank Dr. Wenlin Huang (Sun Yat-sen University) for providing the
pcDNA3.1-SARS-CoV-S plasmid. We thank Dr. Linqi Zhang (Tsinghua University) and Dr.
Shibo Jiang (Fudan University) for providing the pcDNA3.1-MERS-CoV-S plasmid. We
thank Dr. Jun Li (Sun Yat-sen University) for providing the primary human umbilical
vein endothelial cells. We thank Dr. Thomas Hoenen (Federal Research Institute for
Animal Health, Germany) for providing several plasmids to generate trVLPs.</p></ack><ref-list><title>References</title><ref id="B1"><label>1.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Kiley</surname><given-names>M.
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