A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike
Identifieur interne : 001142 ( Pmc/Curation ); précédent : 001141; suivant : 001143A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike
Auteurs : Shuai Xia [République populaire de Chine] ; Lei Yan [République populaire de Chine] ; Wei Xu [République populaire de Chine] ; Anurodh Shankar Agrawal [États-Unis] ; Abdullah Algaissi [États-Unis, Arabie saoudite] ; Chien-Te K. Tseng [États-Unis] ; Qian Wang [République populaire de Chine] ; Lanying Du [États-Unis] ; Wenjie Tan [République populaire de Chine] ; Ian A. Wilson [République populaire de Chine, États-Unis] ; Shibo Jiang [République populaire de Chine, États-Unis] ; Bei Yang [République populaire de Chine] ; Lu Lu [République populaire de Chine]Source :
- Science Advances [ 2375-2548 ] ; 2019.
Abstract
EK1 is a broad-spectrum human coronavirus fusion inhibitor for combating infection of current and emerging coronaviruses.
Url:
DOI: 10.1126/sciadv.aav4580
PubMed: 30989115
PubMed Central: 6457931
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Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Lindsley F. 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wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30989115</idno><idno type="pmc">6457931</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457931</idno><idno type="RBID">PMC:6457931</idno><idno type="doi">10.1126/sciadv.aav4580</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">001142</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001142</idno><idno type="wicri:Area/Pmc/Curation">001142</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001142</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike</title><author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name><affiliation wicri:level="1"><nlm:aff id="aff1">Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032</wicri:regionArea></affiliation></author><author><name sortKey="Yan, Lei" sort="Yan, Lei" uniqKey="Yan L" first="Lei" last="Yan">Lei Yan</name><affiliation wicri:level="1"><nlm:aff id="aff2">Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210</wicri:regionArea></affiliation></author><author><name sortKey="Xu, Wei" sort="Xu, Wei" uniqKey="Xu W" first="Wei" last="Xu">Wei Xu</name><affiliation wicri:level="1"><nlm:aff id="aff1">Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032</wicri:regionArea></affiliation></author><author><name sortKey="Agrawal, Anurodh Shankar" sort="Agrawal, Anurodh Shankar" uniqKey="Agrawal A" first="Anurodh Shankar" last="Agrawal">Anurodh Shankar Agrawal</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555</wicri:regionArea></affiliation></author><author><name sortKey="Algaissi, Abdullah" sort="Algaissi, Abdullah" uniqKey="Algaissi A" first="Abdullah" last="Algaissi">Abdullah Algaissi</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4">Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.</nlm:aff><country xml:lang="fr" wicri:curation="lc">Arabie saoudite</country><wicri:regionArea>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan</wicri:regionArea></affiliation></author><author><name sortKey="Tseng, Chien Te K" sort="Tseng, Chien Te K" uniqKey="Tseng C" first="Chien-Te K." last="Tseng">Chien-Te K. Tseng</name><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1">Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032</wicri:regionArea></affiliation></author><author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name><affiliation wicri:level="1"><nlm:aff id="aff5">Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065</wicri:regionArea></affiliation></author><author><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><affiliation wicri:level="1"><nlm:aff id="aff6">MOH Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>MOH Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name><affiliation wicri:level="1"><nlm:aff id="aff2">Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff7">Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC206, La Jolla, CA 92037, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC206, La Jolla, CA 92037</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation wicri:level="1"><nlm:aff id="aff1">Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5">Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Bei" sort="Yang, Bei" uniqKey="Yang B" first="Bei" last="Yang">Bei Yang</name><affiliation wicri:level="1"><nlm:aff id="aff2">Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210</wicri:regionArea></affiliation></author><author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name><affiliation wicri:level="1"><nlm:aff id="aff1">Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032</wicri:regionArea></affiliation></author></analytic><series><title level="j">Science Advances</title><idno type="eISSN">2375-2548</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>EK1 is a broad-spectrum human coronavirus fusion inhibitor for combating infection of current and emerging coronaviruses.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Woo, P C Y" uniqKey="Woo P">P. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Sci Adv</journal-id><journal-id journal-id-type="iso-abbrev">Sci Adv</journal-id><journal-id journal-id-type="publisher-id">SciAdv</journal-id><journal-id journal-id-type="hwp">advances</journal-id><journal-title-group><journal-title>Science Advances</journal-title></journal-title-group><issn pub-type="epub">2375-2548</issn><publisher><publisher-name>American Association for the Advancement of Science</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30989115</article-id><article-id pub-id-type="pmc">6457931</article-id><article-id pub-id-type="publisher-id">aav4580</article-id><article-id pub-id-type="doi">10.1126/sciadv.aav4580</article-id><article-categories><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group><subj-group subj-group-type="heading"><subject>Research Articles</subject></subj-group><subj-group subj-group-type="legacy-article-type"><subject>SciAdv r-articles</subject></subj-group><subj-group subj-group-type="field"><subject>Biochemistry</subject><subject>Virology</subject></subj-group><subj-group subj-group-type="overline"><subject>Biochemistry</subject></subj-group></article-categories><title-group><article-title>A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0001-7896-4182</contrib-id><name><surname>Xia</surname><given-names>Shuai</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="afn1">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0003-1775-5533</contrib-id><name><surname>Yan</surname><given-names>Lei</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="author-notes" rid="afn1">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0003-3013-7182</contrib-id><name><surname>Xu</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="afn1">*</xref></contrib><contrib contrib-type="author"><name><surname>Agrawal</surname><given-names>Anurodh Shankar</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Algaissi</surname><given-names>Abdullah</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tseng</surname><given-names>Chien-Te K.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Qian</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Du</surname><given-names>Lanying</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Wenjie</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-6469-2419</contrib-id><name><surname>Wilson</surname><given-names>Ian A.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref rid="cor1" ref-type="corresp">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0003-1493-6523</contrib-id><name><surname>Jiang</surname><given-names>Shibo</given-names></name><xref ref-type="award" rid="award427216"></xref><xref ref-type="award" rid="award427237"></xref><xref ref-type="award" rid="award427217"></xref><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref rid="cor1" ref-type="corresp">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0001-5389-3859</contrib-id><name><surname>Yang</surname><given-names>Bei</given-names></name><xref ref-type="award" rid="award427256"></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref rid="cor1" ref-type="corresp">†</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-2255-0391</contrib-id><name><surname>Lu</surname><given-names>Lu</given-names></name><xref ref-type="award" rid="award427252"></xref><xref ref-type="award" rid="award427254"></xref><xref ref-type="award" rid="award427255"></xref><xref ref-type="award" rid="award427218"></xref><xref ref-type="award" rid="award427872"></xref><xref ref-type="award" rid="award427215"></xref><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref rid="cor1" ref-type="corresp">†</xref></contrib><aff id="aff1"><label>1</label>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</aff><aff id="aff2"><label>2</label>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</aff><aff id="aff3"><label>3</label>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</aff><aff id="aff4"><label>4</label>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.</aff><aff id="aff5"><label>5</label>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</aff><aff id="aff6"><label>6</label>MOH Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.</aff><aff id="aff7"><label>7</label>Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC206, La Jolla, CA 92037, USA.</aff></contrib-group><author-notes><fn id="afn1" fn-type="equal"><label>*</label><p>These authors contributed equally to this work.</p></fn><corresp id="cor1"><label>†</label>Corresponding author. Email: <email xlink:href="wilson@scripps.edu">wilson@scripps.edu</email> (I.A.W.); <email xlink:href="shibojiang@fudan.edu.cn">shibojiang@fudan.edu.cn</email> (S.J.); <email xlink:href="yangbei@shanghaitech.edu.cn">yangbei@shanghaitech.edu.cn</email> (B.Y.); <email xlink:href="lul@fudan.edu.cn">lul@fudan.edu.cn</email> (L.L.)</corresp></author-notes><pub-date pub-type="collection"><month>4</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>10</day><month>4</month><year>2019</year></pub-date><volume>5</volume><issue>4</issue><elocation-id>eaav4580</elocation-id><history><date date-type="received"><day>25</day><month>9</month><year>2018</year></date><date date-type="accepted"><day>14</day><month>2</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>The Authors</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/" id="p-2"><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/4.0/">Creative Commons Attribution-NonCommercial license</ext-link>, which permits use, distribution, and reproduction in any medium, so long as the resultant use is <bold>not</bold> for commercial advantage and provided the original work is properly cited.</license-p></license></permissions><abstract abstract-type="teaser"><p>EK1 is a broad-spectrum human coronavirus fusion inhibitor for combating infection of current and emerging coronaviruses.</p></abstract><abstract><p>Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.</p></abstract><funding-group><award-group id="award427252"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81661128041</award-id></award-group><award-group id="award427254"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81672019</award-id></award-group><award-group id="award427255"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81822045</award-id></award-group><award-group id="award427256"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>31600619</award-id></award-group><award-group id="award427216"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100002855</institution-id><institution>Ministry of Science and Technology of the People’s Republic of China</institution></institution-wrap></funding-source><award-id>2016YFC1201000</award-id></award-group><award-group id="award427218"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100002855</institution-id><institution>Ministry of Science and Technology of the People’s Republic of China</institution></institution-wrap></funding-source><award-id>2016YFC1202901</award-id></award-group><award-group id="award427872"><funding-source><institution-wrap><institution>the Shanghai Rising-Star Program</institution></institution-wrap></funding-source><award-id>16QA1400300</award-id></award-group><award-group id="award427215"><funding-source><institution-wrap><institution>National Megaprojects of China for Major Infectious Diseases</institution></institution-wrap></funding-source><award-id>2018ZX10301403</award-id></award-group><award-group id="award427237"><funding-source><institution-wrap><institution>The Sanming Project of Medicine in Shenzhen</institution></institution-wrap></funding-source></award-group><award-group id="award427217"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100002855</institution-id><institution>Ministry of Science and Technology of the People’s Republic of China</institution></institution-wrap></funding-source><award-id>2016YFC1200405</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>Copyeditor</meta-name><meta-value>Eunice Ann Alesin</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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