Article ; Online: 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.
2020 Volume 30, Issue 4, Page(s) 343–355
Abstract: ... the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus ... with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1 ... Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV ...
| 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. |
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| MeSH term(s) | Administration, Intranasal ; Amino Acid Sequence ; Animals ; Betacoronavirus/drug effects ; Betacoronavirus/physiology ; COVID-19 ; 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 ; Severe acute respiratory syndrome-related coronavirus ; SARS-CoV-2 ; Sequence Alignment ; Spike Glycoprotein, Coronavirus/antagonists & inhibitors ; Structure-Activity Relationship ; Vero Cells |
| Chemical Substances | Lipopeptides ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 |
| Keywords | covid19 |
| Language | English |
| Publishing date | 2020-03-30 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 1319303-x |
| ISSN | 1748-7838 ; 1001-0602 |
| ISSN (online) | 1748-7838 |
| ISSN | 1001-0602 |
| DOI | 10.1038/s41422-020-0305-x |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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