Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
Identifieur interne : 000346 ( Pmc/Curation ); précédent : 000345; suivant : 000347Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
Auteurs : Shuai Xia [République populaire de Chine] ; Meiqin Liu [République populaire de Chine] ; Chao Wang [République populaire de Chine] ; Wei Xu [République populaire de Chine] ; Qiaoshuai Lan [République populaire de Chine] ; Siliang Feng [République populaire de Chine] ; Feifei Qi [République populaire de Chine] ; Linlin Bao [République populaire de Chine] ; Lanying Du [États-Unis] ; Shuwen Liu [République populaire de Chine] ; Chuan Qin [République populaire de Chine] ; Fei Sun [République populaire de Chine] ; Zhengli Shi [République populaire de Chine] ; Yun Zhu [République populaire de Chine] ; Shibo Jiang [République populaire de Chine, États-Unis] ; Lu Lu [République populaire de Chine]Source :
- Cell Research [ 1001-0602 ] ; 2020.
Abstract
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
Url:
DOI: 10.1038/s41422-020-0305-x
PubMed: NONE
PubMed Central: 7104723
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<author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name>
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<author><name sortKey="Wang, Chao" sort="Wang, Chao" uniqKey="Wang C" first="Chao" last="Wang">Chao Wang</name>
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<author><name sortKey="Lan, Qiaoshuai" sort="Lan, Qiaoshuai" uniqKey="Lan Q" first="Qiaoshuai" last="Lan">Qiaoshuai Lan</name>
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<author><name sortKey="Feng, Siliang" sort="Feng, Siliang" uniqKey="Feng S" first="Siliang" last="Feng">Siliang Feng</name>
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27 Tai-Ping Road, Beijing, 100850 China</nlm:aff>
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<author><name sortKey="Qi, Feifei" sort="Qi, Feifei" uniqKey="Qi F" first="Feifei" last="Qi">Feifei Qi</name>
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<author><name sortKey="Bao, Linlin" sort="Bao, Linlin" uniqKey="Bao L" first="Linlin" last="Bao">Linlin Bao</name>
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Beijing, 100021 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
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</author>
<author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name>
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<institution-id institution-id-type="GRID">grid.250415.7</institution-id>
<institution>Lindsley F. Kimball Research Institute, New York Blood Center,</institution>
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New York, NY 10065 USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>New York</wicri:cityArea>
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</author>
<author><name sortKey="Liu, Shuwen" sort="Liu, Shuwen" uniqKey="Liu S" first="Shuwen" last="Liu">Shuwen Liu</name>
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<institution>Guangdong Provincial Key Laboratory of New Drug Screening,</institution>
<institution>Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University,</institution>
</institution-wrap>
Guangzhou, 510515 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Guangzhou</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Qin, Chuan" sort="Qin, Chuan" uniqKey="Qin C" first="Chuan" last="Qin">Chuan Qin</name>
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<institution-id institution-id-type="GRID">grid.12527.33</institution-id>
<institution>Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center,</institution>
<institution>Peking Union Medical College,</institution>
</institution-wrap>
Beijing, 100021 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sun, Fei" sort="Sun, Fei" uniqKey="Sun F" first="Fei" last="Sun">Fei Sun</name>
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<institution-id institution-id-type="GRID">grid.418856.6</institution-id>
<institution>National Laboratory of Biomacromolecules,</institution>
<institution>Institute of Biophysics, Chinese Academy of Sciences,</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Shi, Zhengli" sort="Shi, Zhengli" uniqKey="Shi Z" first="Zhengli" last="Shi">Zhengli Shi</name>
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<institution-id institution-id-type="GRID">grid.9227.e</institution-id>
<institution>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science,</institution>
<institution>Chinese Academy of Sciences,</institution>
</institution-wrap>
Wuhan, 430071 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Wuhan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zhu, Yun" sort="Zhu, Yun" uniqKey="Zhu Y" first="Yun" last="Zhu">Yun Zhu</name>
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<institution-id institution-id-type="GRID">grid.418856.6</institution-id>
<institution>National Laboratory of Biomacromolecules,</institution>
<institution>Institute of Biophysics, Chinese Academy of Sciences,</institution>
</institution-wrap>
Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
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<institution>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center,</institution>
<institution>Fudan University,</institution>
</institution-wrap>
Shanghai, 200032 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Shanghai</wicri:regionArea>
</affiliation>
<affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0442 2075</institution-id>
<institution-id institution-id-type="GRID">grid.250415.7</institution-id>
<institution>Lindsley F. Kimball Research Institute, New York Blood Center,</institution>
</institution-wrap>
New York, NY 10065 USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">État de New York</region>
</placeName>
<wicri:cityArea>New York</wicri:cityArea>
</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"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0125 2443</institution-id>
<institution-id institution-id-type="GRID">grid.8547.e</institution-id>
<institution>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center,</institution>
<institution>Fudan University,</institution>
</institution-wrap>
Shanghai, 200032 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Shanghai</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Research</title>
<idno type="ISSN">1001-0602</idno>
<idno type="eISSN">1748-7838</idno>
<imprint><date when="2020">2020</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p id="Par1">The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.</p>
</div>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Res</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Res</journal-id>
<journal-title-group><journal-title>Cell Research</journal-title>
</journal-title-group>
<issn pub-type="ppub">1001-0602</issn>
<issn pub-type="epub">1748-7838</issn>
<publisher><publisher-name>Springer Singapore</publisher-name>
<publisher-loc>Singapore</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmc">7104723</article-id>
<article-id pub-id-type="publisher-id">305</article-id>
<article-id pub-id-type="doi">10.1038/s41422-020-0305-x</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Xia</surname>
<given-names>Shuai</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Liu</surname>
<given-names>Meiqin</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Wang</surname>
<given-names>Chao</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Xu</surname>
<given-names>Wei</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-5524-3542</contrib-id>
<name><surname>Lan</surname>
<given-names>Qiaoshuai</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feng</surname>
<given-names>Siliang</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Qi</surname>
<given-names>Feifei</given-names>
</name>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bao</surname>
<given-names>Linlin</given-names>
</name>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Du</surname>
<given-names>Lanying</given-names>
</name>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Shuwen</given-names>
</name>
<xref ref-type="aff" rid="Aff7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Qin</surname>
<given-names>Chuan</given-names>
</name>
<xref ref-type="aff" rid="Aff5">5</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-0351-5144</contrib-id>
<name><surname>Sun</surname>
<given-names>Fei</given-names>
</name>
<xref ref-type="aff" rid="Aff8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shi</surname>
<given-names>Zhengli</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Zhu</surname>
<given-names>Yun</given-names>
</name>
<address><email>zhuyun@ibp.ac.cn</email>
</address>
<xref ref-type="aff" rid="Aff8">8</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Jiang</surname>
<given-names>Shibo</given-names>
</name>
<address><email>shibojiang@fudan.edu.cn</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff6">6</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0002-2255-0391</contrib-id>
<name><surname>Lu</surname>
<given-names>Lu</given-names>
</name>
<address><email>lul@fudan.edu.cn</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0125 2443</institution-id>
<institution-id institution-id-type="GRID">grid.8547.e</institution-id>
<institution>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center,</institution>
<institution>Fudan University,</institution>
</institution-wrap>
Shanghai, 200032 China</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000000119573309</institution-id>
<institution-id institution-id-type="GRID">grid.9227.e</institution-id>
<institution>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science,</institution>
<institution>Chinese Academy of Sciences,</institution>
</institution-wrap>
Wuhan, 430071 China</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 8419</institution-id>
<institution-id institution-id-type="GRID">grid.410726.6</institution-id>
<institution>University of Chinese Academy of Sciences,</institution>
</institution-wrap>
Beijing, 100190 China</aff>
<aff id="Aff4"><label>4</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1803 4911</institution-id>
<institution-id institution-id-type="GRID">grid.410740.6</institution-id>
<institution>State Key Laboratory of Toxicology and Medical Countermeasures,</institution>
<institution>Beijing Institute of Pharmacology and Toxicology,</institution>
</institution-wrap>
27 Tai-Ping Road, Beijing, 100850 China</aff>
<aff id="Aff5"><label>5</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0662 3178</institution-id>
<institution-id institution-id-type="GRID">grid.12527.33</institution-id>
<institution>Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center,</institution>
<institution>Peking Union Medical College,</institution>
</institution-wrap>
Beijing, 100021 China</aff>
<aff id="Aff6"><label>6</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0442 2075</institution-id>
<institution-id institution-id-type="GRID">grid.250415.7</institution-id>
<institution>Lindsley F. Kimball Research Institute, New York Blood Center,</institution>
</institution-wrap>
New York, NY 10065 USA</aff>
<aff id="Aff7"><label>7</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0000 8877 7471</institution-id>
<institution-id institution-id-type="GRID">grid.284723.8</institution-id>
<institution>Guangdong Provincial Key Laboratory of New Drug Screening,</institution>
<institution>Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University,</institution>
</institution-wrap>
Guangzhou, 510515 China</aff>
<aff id="Aff8"><label>8</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1792 5640</institution-id>
<institution-id institution-id-type="GRID">grid.418856.6</institution-id>
<institution>National Laboratory of Biomacromolecules,</institution>
<institution>Institute of Biophysics, Chinese Academy of Sciences,</institution>
</institution-wrap>
Beijing, 100101 China</aff>
</contrib-group>
<pub-date pub-type="epub"><day>30</day>
<month>3</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>30</day>
<month>3</month>
<year>2020</year>
</pub-date>
<fpage>1</fpage>
<lpage>13</lpage>
<history><date date-type="received"><day>25</day>
<month>2</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>10</day>
<month>3</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s) 2020</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
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</permissions>
<abstract id="Abs1"><p id="Par1">The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.</p>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>Membrane fusion</kwd>
<kwd>Electron microscopy</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution>National Megaprojects of China for Major Infectious Diseases (2018ZX10301403);The National Natural Science Foundation of China (81822045)</institution>
</funding-source>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100002858</institution-id>
<institution>China Postdoctoral Science Foundation</institution>
</institution-wrap>
</funding-source>
<award-id>2018M640341 and 2019T120302</award-id>
<principal-award-recipient><name><surname>Xia</surname>
<given-names>Shuai</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>The National Natural Science Foundation of China (81703571)</institution>
</funding-source>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>the National Key Research and Development Program of China (2018YFA0901102 & 2019YFA0904101)</institution>
</funding-source>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution>The National Natural Science Foundation of China (81630090)</institution>
</funding-source>
</award-group>
</funding-group>
</article-meta>
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