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Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Shuai Xia, Meiqin Liu, Chao Wang, Wei Xu, Qiaoshuai Lan, Siliang Feng, Feifei Qi, Linlin Bao, Lanying Du, Shuwen Liu, Chuan Qin, View ORCID ProfileFei Sun, Zhengli Shi, Yun Zhu, Shibo Jiang, Lu Lu
doi: https://doi.org/10.1101/2020.03.09.983247
Shuai Xia
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, China
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Meiqin Liu
2CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
8University of Chinese Academy of Sciences, Beijing, People’s Republic of China
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Chao Wang
4State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
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Wei Xu
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, China
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Qiaoshuai Lan
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, China
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Siliang Feng
4State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
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Feifei Qi
5Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Re-emerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
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Linlin Bao
5Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Re-emerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
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Lanying Du
6Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA
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Shuwen Liu
7Guangdong 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, China
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Chuan Qin
5Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Re-emerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
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Fei Sun
3National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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  • ORCID record for Fei Sun
  • For correspondence: feisun@ibp.ac.cn zlshi@wh.iov.cn zhuyun@ibp.ac.cn shibojiang@fudan.edu.cn lul@fudan.edu.cn
Zhengli Shi
2CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China
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  • For correspondence: feisun@ibp.ac.cn zlshi@wh.iov.cn zhuyun@ibp.ac.cn shibojiang@fudan.edu.cn lul@fudan.edu.cn
Yun Zhu
3National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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  • For correspondence: feisun@ibp.ac.cn zlshi@wh.iov.cn zhuyun@ibp.ac.cn shibojiang@fudan.edu.cn lul@fudan.edu.cn
Shibo Jiang
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, China
6Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, USA
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  • For correspondence: feisun@ibp.ac.cn zlshi@wh.iov.cn zhuyun@ibp.ac.cn shibojiang@fudan.edu.cn lul@fudan.edu.cn
Lu Lu
1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, China
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  • For correspondence: feisun@ibp.ac.cn zlshi@wh.iov.cn zhuyun@ibp.ac.cn shibojiang@fudan.edu.cn lul@fudan.edu.cn
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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 confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior 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 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 HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the 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 that of 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, potently inhibiting replication of 4 live human coronaviruses, 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 currently circulating SARS-CoV-2 and emerging SARSr-CoVs.

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Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
Shuai Xia, Meiqin Liu, Chao Wang, Wei Xu, Qiaoshuai Lan, Siliang Feng, Feifei Qi, Linlin Bao, Lanying Du, Shuwen Liu, Chuan Qin, Fei Sun, Zhengli Shi, Yun Zhu, Shibo Jiang, Lu Lu
bioRxiv 2020.03.09.983247; doi: https://doi.org/10.1101/2020.03.09.983247
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Inhibition of SARS-CoV-2 infection (previously 2019-nCoV) by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
Shuai Xia, Meiqin Liu, Chao Wang, Wei Xu, Qiaoshuai Lan, Siliang Feng, Feifei Qi, Linlin Bao, Lanying Du, Shuwen Liu, Chuan Qin, Fei Sun, Zhengli Shi, Yun Zhu, Shibo Jiang, Lu Lu
bioRxiv 2020.03.09.983247; doi: https://doi.org/10.1101/2020.03.09.983247

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