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 : 000107 ( PubMed/Curation ); précédent : 000106; suivant : 000108Inhibition 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] ; Lu Lu [République populaire de Chine]Source :
- Cell research [ 1748-7838 ] ; 2020.
Descripteurs français
- KwdFr :
- Administration par voie nasale, Alignement de séquences, Animaux, Cellules HEK293, Cellules Vero, Fusion cellulaire, Fusion membranaire, Glycoprotéine de spicule des coronavirus (antagonistes et inhibiteurs), Humains, Infections à coronavirus (), Lipopeptides (pharmacologie), Motifs et domaines d'intéraction protéique, Pandémies (), Pneumopathie virale (), Relation structure-activité, Souris, Structure secondaire des protéines, Séquence d'acides aminés, Virus du SRAS.
- MESH :
- antagonistes et inhibiteurs : Glycoprotéine de spicule des coronavirus.
- pharmacologie : Lipopeptides.
- Administration par voie nasale, Alignement de séquences, Animaux, Cellules HEK293, Cellules Vero, Fusion cellulaire, Fusion membranaire, Humains, Infections à coronavirus, Motifs et domaines d'intéraction protéique, Pandémies, Pneumopathie virale, Relation structure-activité, Souris, Structure secondaire des protéines, Séquence d'acides aminés, Virus du SRAS.
English descriptors
- KwdEn :
- Administration, Intranasal, Amino Acid Sequence, Animals, Betacoronavirus (drug effects), Betacoronavirus (physiology), Cell Fusion, Chlorocebus aethiops, Coronavirus Infections (prevention & control), HEK293 Cells, Humans, Lipopeptides (pharmacology), Membrane Fusion, Mice, Pandemics (prevention & control), Pneumonia, Viral (prevention & control), Protein Interaction Domains and Motifs, Protein Structure, Secondary, SARS Virus, Sequence Alignment, Spike Glycoprotein, Coronavirus (antagonists & inhibitors), Structure-Activity Relationship, Vero Cells.
- MESH :
- chemical , antagonists & inhibitors : Spike Glycoprotein, Coronavirus.
- chemical , pharmacology : Lipopeptides.
- drug effects : Betacoronavirus.
- physiology : Betacoronavirus.
- prevention & control : Coronavirus Infections, Pandemics, Pneumonia, Viral.
- Administration, Intranasal, Amino Acid Sequence, Animals, Cell Fusion, Chlorocebus aethiops, HEK293 Cells, Humans, Membrane Fusion, Mice, Protein Interaction Domains and Motifs, Protein Structure, Secondary, SARS Virus, Sequence Alignment, Structure-Activity Relationship, Vero Cells.
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.
DOI: 10.1038/s41422-020-0305-x
PubMed: 32231345
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100850</wicri:regionArea></affiliation></author><author><name sortKey="Qi, Feifei" sort="Qi, Feifei" uniqKey="Qi F" first="Feifei" last="Qi">Feifei Qi</name><affiliation wicri:level="1"><nlm:affiliation>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, Peking Union Medical College, Beijing, 100021, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>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, Peking Union Medical College, Beijing, 100021</wicri:regionArea></affiliation></author><author><name sortKey="Bao, Linlin" sort="Bao, Linlin" uniqKey="Bao L" first="Linlin" last="Bao">Linlin Bao</name><affiliation wicri:level="1"><nlm:affiliation>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, Peking Union Medical College, Beijing, 100021, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>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, Peking Union Medical College, Beijing, 100021</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:affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA.</nlm:affiliation><country xml:lang="fr">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="Liu, Shuwen" sort="Liu, Shuwen" uniqKey="Liu S" first="Shuwen" last="Liu">Shuwen Liu</name><affiliation wicri:level="1"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515</wicri:regionArea></affiliation></author><author><name sortKey="Qin, Chuan" sort="Qin, Chuan" uniqKey="Qin C" first="Chuan" last="Qin">Chuan Qin</name><affiliation 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of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101</wicri:regionArea></affiliation></author><author><name sortKey="Shi, Zhengli" sort="Shi, Zhengli" uniqKey="Shi Z" first="Zhengli" last="Shi">Zhengli Shi</name><affiliation wicri:level="1"><nlm:affiliation>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071</wicri:regionArea></affiliation></author><author><name sortKey="Zhu, Yun" sort="Zhu, Yun" uniqKey="Zhu Y" first="Yun" last="Zhu">Yun Zhu</name><affiliation wicri:level="1"><nlm:affiliation>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhuyun@ibp.ac.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101</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:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China. shibojiang@fudan.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</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:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China. lul@fudan.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32231345</idno><idno type="pmid">32231345</idno><idno type="doi">10.1038/s41422-020-0305-x</idno><idno type="wicri:Area/PubMed/Corpus">000107</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000107</idno><idno type="wicri:Area/PubMed/Curation">000107</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000107</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">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.</title><author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name><affiliation wicri:level="1"><nlm:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</wicri:regionArea></affiliation></author><author><name sortKey="Liu, Meiqin" sort="Liu, Meiqin" uniqKey="Liu M" first="Meiqin" last="Liu">Meiqin Liu</name><affiliation wicri:level="1"><nlm:affiliation>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Chao" sort="Wang, Chao" uniqKey="Wang C" first="Chao" last="Wang">Chao Wang</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850</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:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</wicri:regionArea></affiliation></author><author><name sortKey="Lan, Qiaoshuai" sort="Lan, Qiaoshuai" uniqKey="Lan Q" first="Qiaoshuai" last="Lan">Qiaoshuai Lan</name><affiliation wicri:level="1"><nlm:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</wicri:regionArea></affiliation></author><author><name sortKey="Feng, Siliang" sort="Feng, Siliang" uniqKey="Feng S" first="Siliang" last="Feng">Siliang Feng</name><affiliation wicri:level="1"><nlm:affiliation>State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850</wicri:regionArea></affiliation></author><author><name sortKey="Qi, Feifei" sort="Qi, Feifei" uniqKey="Qi F" first="Feifei" last="Qi">Feifei Qi</name><affiliation wicri:level="1"><nlm:affiliation>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, Peking Union Medical College, Beijing, 100021, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>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, Peking Union Medical College, Beijing, 100021</wicri:regionArea></affiliation></author><author><name sortKey="Bao, Linlin" sort="Bao, Linlin" uniqKey="Bao L" first="Linlin" last="Bao">Linlin Bao</name><affiliation wicri:level="1"><nlm:affiliation>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, Peking Union Medical College, Beijing, 100021, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>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, Peking Union Medical College, Beijing, 100021</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:affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA.</nlm:affiliation><country xml:lang="fr">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="Liu, Shuwen" sort="Liu, Shuwen" uniqKey="Liu S" first="Shuwen" last="Liu">Shuwen Liu</name><affiliation wicri:level="1"><nlm:affiliation>Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515</wicri:regionArea></affiliation></author><author><name sortKey="Qin, Chuan" sort="Qin, Chuan" uniqKey="Qin C" first="Chuan" last="Qin">Chuan Qin</name><affiliation wicri:level="1"><nlm:affiliation>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, Peking Union Medical College, Beijing, 100021, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>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, Peking Union Medical College, Beijing, 100021</wicri:regionArea></affiliation></author><author><name sortKey="Sun, Fei" sort="Sun, Fei" uniqKey="Sun F" first="Fei" last="Sun">Fei Sun</name><affiliation wicri:level="1"><nlm:affiliation>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101</wicri:regionArea></affiliation></author><author><name sortKey="Shi, Zhengli" sort="Shi, Zhengli" uniqKey="Shi Z" first="Zhengli" last="Shi">Zhengli Shi</name><affiliation wicri:level="1"><nlm:affiliation>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071</wicri:regionArea></affiliation></author><author><name sortKey="Zhu, Yun" sort="Zhu, Yun" uniqKey="Zhu Y" first="Yun" last="Zhu">Yun Zhu</name><affiliation wicri:level="1"><nlm:affiliation>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhuyun@ibp.ac.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101</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:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China. shibojiang@fudan.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</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:affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China. lul@fudan.edu.cn.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032</wicri:regionArea></affiliation></author></analytic><series><title level="j">Cell research</title><idno type="eISSN">1748-7838</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Administration, Intranasal</term><term>Amino Acid Sequence</term><term>Animals</term><term>Betacoronavirus (drug effects)</term><term>Betacoronavirus (physiology)</term><term>Cell Fusion</term><term>Chlorocebus aethiops</term><term>Coronavirus Infections (prevention & control)</term><term>HEK293 Cells</term><term>Humans</term><term>Lipopeptides (pharmacology)</term><term>Membrane Fusion</term><term>Mice</term><term>Pandemics (prevention & control)</term><term>Pneumonia, Viral (prevention & control)</term><term>Protein Interaction Domains and Motifs</term><term>Protein Structure, Secondary</term><term>SARS Virus</term><term>Sequence Alignment</term><term>Spike Glycoprotein, Coronavirus (antagonists & inhibitors)</term><term>Structure-Activity Relationship</term><term>Vero Cells</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Administration par voie nasale</term><term>Alignement de séquences</term><term>Animaux</term><term>Cellules HEK293</term><term>Cellules Vero</term><term>Fusion cellulaire</term><term>Fusion membranaire</term><term>Glycoprotéine de spicule des coronavirus (antagonistes et inhibiteurs)</term><term>Humains</term><term>Infections à coronavirus ()</term><term>Lipopeptides (pharmacologie)</term><term>Motifs et domaines d'intéraction protéique</term><term>Pandémies ()</term><term>Pneumopathie virale ()</term><term>Relation structure-activité</term><term>Souris</term><term>Structure secondaire des protéines</term><term>Séquence d'acides aminés</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Spike Glycoprotein, Coronavirus</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Lipopeptides</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Glycoprotéine de spicule des coronavirus</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Lipopeptides</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Betacoronavirus</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Coronavirus Infections</term><term>Pandemics</term><term>Pneumonia, Viral</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Administration, Intranasal</term><term>Amino Acid Sequence</term><term>Animals</term><term>Cell Fusion</term><term>Chlorocebus aethiops</term><term>HEK293 Cells</term><term>Humans</term><term>Membrane Fusion</term><term>Mice</term><term>Protein Interaction Domains and Motifs</term><term>Protein Structure, Secondary</term><term>SARS Virus</term><term>Sequence Alignment</term><term>Structure-Activity Relationship</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Administration par voie nasale</term><term>Alignement de séquences</term><term>Animaux</term><term>Cellules HEK293</term><term>Cellules Vero</term><term>Fusion cellulaire</term><term>Fusion membranaire</term><term>Humains</term><term>Infections à coronavirus</term><term>Motifs et domaines d'intéraction protéique</term><term>Pandémies</term><term>Pneumopathie virale</term><term>Relation structure-activité</term><term>Souris</term><term>Structure secondaire des protéines</term><term>Séquence d'acides aminés</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">32231345</PMID><DateCompleted><Year>2020</Year><Month>04</Month><Day>07</Day></DateCompleted><DateRevised><Year>2020</Year><Month>04</Month><Day>08</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1748-7838</ISSN><JournalIssue CitedMedium="Internet"><Volume>30</Volume><Issue>4</Issue><PubDate><Year>2020</Year><Month>Apr</Month></PubDate></JournalIssue><Title>Cell research</Title><ISOAbbreviation>Cell Res.</ISOAbbreviation></Journal><ArticleTitle>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.</ArticleTitle><Pagination><MedlinePgn>343-355</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/s41422-020-0305-x</ELocationID><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Xia</LastName><ForeName>Shuai</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Meiqin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>University of Chinese Academy of Sciences, Beijing, 100190, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Chao</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xu</LastName><ForeName>Wei</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lan</LastName><ForeName>Qiaoshuai</ForeName><Initials>Q</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-5524-3542</Identifier><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Feng</LastName><ForeName>Siliang</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Qi</LastName><ForeName>Feifei</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>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, Peking Union Medical College, Beijing, 100021, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bao</LastName><ForeName>Linlin</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>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, Peking Union Medical College, Beijing, 100021, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Du</LastName><ForeName>Lanying</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Liu</LastName><ForeName>Shuwen</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Qin</LastName><ForeName>Chuan</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>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, Peking Union Medical College, Beijing, 100021, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sun</LastName><ForeName>Fei</ForeName><Initials>F</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-0351-5144</Identifier><AffiliationInfo><Affiliation>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shi</LastName><ForeName>Zhengli</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zhu</LastName><ForeName>Yun</ForeName><Initials>Y</Initials><AffiliationInfo><Affiliation>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhuyun@ibp.ac.cn.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jiang</LastName><ForeName>Shibo</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China. shibojiang@fudan.edu.cn.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA. shibojiang@fudan.edu.cn.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Lu</ForeName><Initials>L</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-2255-0391</Identifier><AffiliationInfo><Affiliation>Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China. lul@fudan.edu.cn.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>2018M640341 and 2019T120302</GrantID><Agency>China Postdoctoral Science Foundation</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>03</Month><Day>30</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Cell Res</MedlineTA><NlmUniqueID>9425763</NlmUniqueID><ISSNLinking>1001-0602</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D055666">Lipopeptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D064370">Spike Glycoprotein, Coronavirus</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C000657845">spike glycoprotein, COVID-19 virus</NameOfSubstance></Chemical></ChemicalList><SupplMeshList><SupplMeshName Type="Disease" UI="C000657245">COVID-19</SupplMeshName><SupplMeshName Type="Organism" UI="C000656484">severe acute respiratory syndrome coronavirus 2</SupplMeshName></SupplMeshList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000281" MajorTopicYN="N">Administration, Intranasal</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000595" MajorTopicYN="N">Amino Acid Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000073640" MajorTopicYN="N">Betacoronavirus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002459" MajorTopicYN="N">Cell Fusion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018352" MajorTopicYN="N">Coronavirus Infections</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D057809" MajorTopicYN="N">HEK293 Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D055666" MajorTopicYN="N">Lipopeptides</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008561" MajorTopicYN="Y">Membrane Fusion</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D058873" MajorTopicYN="N">Pandemics</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011024" MajorTopicYN="N">Pneumonia, Viral</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D054730" MajorTopicYN="N">Protein Interaction Domains and 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HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Curation/RBID.i -Sk "pubmed:32231345" \
| HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd \
| NlmPubMed2Wicri -a MersV1
| This area was generated with Dilib version V0.6.33. |  |