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

By Shuai Xia, Meiqin Liu, Chao Wang, W. Xu, Qiaoshuai Lan, Siliang Feng, Feifei Qi, L. Bao, L. Du, Shuwen Liu and 6 more. Cell Research, 2020

1,217 citations recorded by the source corpus.

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.

Subfields: Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/fb030202bbf50ba56922ea88b06dc78327028b26

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. S. Pöhlmann
2. Fang Li
3. M. Hoffmann

In Infectious Diseases

1. J. Shang
2. Yushun Wan
3. Q. Geng
4. S. Pöhlmann
5. Fang Li
6. M. Hoffmann

Citations in the corpus

• Cell entry mechanisms of SARS-CoV-2 (2020, result): “in contrast, the same sera bind SARS-CoV RBD with high affinity and neutralize SARS-CoV pseudovirus entry potently (44).”
• SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development (2020, background): “The six-helical bundle (6-HB) is formed by HR1 and HR2 and is critical for membrane fusion which is dominated by the spike protein of SARS-CoV or SARS-CoV-2, making HR1 and HR2 an attractive drug target (Liu et al., 2004; Xia et al., 2020b).”
• Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia (2020, background): “9,10 To protect against SARS-CoV-2 infection, it is important to form neutralising antibodies targeting S1 RBD, S1 N-terminal domain, or the S2 region; these antibodies block binding of the RBD to the ACE2 receptor and prevent S2-mediated membrane fusion or entry into the host cell, thus inhibiting…”
• Molecular Architecture of the SARS-CoV-2 Virus (2020, background): “They may also come from syncytium naturally formed on infected cells (36), when budding progeny virions carried a few residual postfusion spikes from the cell surface.”
• SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies (2021, positive): “Finally, the membrane fusion inhibitor EK-1 and its optimized lipid-conjugated derivative EK-1-C4 block SARS-CoV-2 entry by preventing conformational rearrangements in the S protein that are required for membrane fusion (Xia et al., 2020).”
• Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease (2020, background): “Compounds that target any of these viral proteins might be potential antiviral drug candidates.(6,7) In this study, we focus on the viral 3CL protease, also called the main protease (M), and aim to develop potent M inhibitors as SARCoV-2 antivirals.”
• Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus (2020, positive): “The fusion core of HR1 (Xia et al., 2020), next to the helix break in pre-fusion Spike, also contains a cluster of amino acid changes between 936-940 (Figure 4E).”