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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.
Cell Res. 2020 Apr; 30(4):343-355.CR

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.

Authors+Show Affiliations

Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China. University of Chinese Academy of Sciences, Beijing, 100190, China.State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan-Jinbo Joint Research Center, Fudan University, Shanghai, 200032, China.State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.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.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.Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA.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.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.National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.CAS Key Laboratory of Special Pathogens, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhuyun@ibp.ac.cn.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. Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY, 10065, USA. shibojiang@fudan.edu.cn.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32231345

Citation

Xia, Shuai, et al. "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." Cell Research, vol. 30, no. 4, 2020, pp. 343-355.
Xia S, Liu M, Wang C, et al. 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. Cell Res. 2020;30(4):343-355.
Xia, S., Liu, M., Wang, C., Xu, W., Lan, Q., Feng, S., Qi, F., Bao, L., Du, L., Liu, S., Qin, C., Sun, F., Shi, Z., Zhu, Y., Jiang, S., & Lu, L. (2020). 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. Cell Research, 30(4), 343-355. https://doi.org/10.1038/s41422-020-0305-x
Xia S, et al. 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. Cell Res. 2020;30(4):343-355. PubMed PMID: 32231345.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Xia,Shuai, AU - Liu,Meiqin, AU - Wang,Chao, AU - Xu,Wei, AU - Lan,Qiaoshuai, AU - Feng,Siliang, AU - Qi,Feifei, AU - Bao,Linlin, AU - Du,Lanying, AU - Liu,Shuwen, AU - Qin,Chuan, AU - Sun,Fei, AU - Shi,Zhengli, AU - Zhu,Yun, AU - Jiang,Shibo, AU - Lu,Lu, Y1 - 2020/03/30/ PY - 2020/02/25/received PY - 2020/03/10/accepted PY - 2020/4/2/pubmed PY - 2020/4/9/medline PY - 2020/4/2/entrez SP - 343 EP - 355 JF - Cell research JO - Cell Res. VL - 30 IS - 4 N2 - 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. SN - 1748-7838 UR - https://www.unboundmedicine.com/medline/citation/32231345/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_ L2 - http://dx.doi.org/10.1038/s41422-020-0305-x DB - PRIME DP - Unbound Medicine ER -