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

Original Article: 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 and Lu Lu, 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

Author of summary: Claudia Foray; Reviewer: Agnese Loda

Original Article Published on March 30th, 2020

In this study the authors describe the role of the membrane fusion mechanism by spike proteins, at the basis of SARS-CoV2 infection. They demonstrate, in vitro and in vivo, the efficacy of the inhibition of HR1 domain of SARS-CoV2 spike proteins using lipopeptides (in particular EK1C4) which, by blocking the fusion mechanism, protect against viral SARS-CoV2 infection.

In order to develop drugs against SARS-CoV2 it is necessary to understand the mechanism underlying the viral infection. As reported in other studies, SARS-CoV2 uses the ACE2 receptor to infect human cells. Once the receptor-binding domain (RBD) of subunit 1 of the spike protein of the virion binds to the ACE2 receptor on the target cell, the HR1 and HR2 domains of the second subunit form a 6 helix bundle, bringing the cell and virus membranes close together to facilitate fusion and infection. Unlike SARS-CoV, SARS-CoV2-infected cells form typical syncytium, suggesting that SARS-CoV2 uses the plasma membrane fusion pathway to infect and replicate within the host cells, rather than the endosomal membrane fusion pathway used by  SARS-CoV. Notably,  this difference seems to contribute to the higher infectivity and transmissibility of SARS-CoV2 compared to SARS-CoV. Analysis of the cell fusion mechanism mediated by the spike proteins of SARS-CoV2 showed that the higher fusion capacity of SARS-CoV2 is probably due to the presence of the S1/S2 cleavage site between the subunits S1 and S2 of the SARS-CoV2 spike protein, which is generally missing in β-B type coronaviruses such as SARS-CoV. As explained at the beginning, in human coronaviruses a key role during the membrane fusion process is played by the HR1 and HR2 domains of the second subunit of the spike proteins. Using X-ray crystallography, the authors found several mutated residues in the HR1 domain of SARS-CoV2 compared to SARS-CoV. These differences leads to an increase in the binding affinity of HR1 to HR2 and to higher efficiency of the membrane fusion process, which therefore increases the infectivity and transmissibility of the virus. Starting from a molecule previously developed by the same group, a pan-coronavirus fusion inhibitor called EK1, whose target is the HR1 domain, the authors have generated a number of new molecules with the aim of increasing the inhibitory action of EK1. EK1C4 was found to be the most powerful lipopeptide against SARS-CoV2 spike proteins and pseudo-virus infection, with an IC50 of 1.3 and 15.8 nM. EK1C4 was also the most effective in inhibiting membrane fusion of other human pseudo-coronaviruses, including SARS-Cov and MERS-CoV, and potentially inhibits replication of 5 tested human coronaviruses, including SARS-CoV2, as suggested by in vitro infection assays. Intrananasal application of EK1C4 in mouse models, shortly before (0.5-1 hour) or shortly after (0.5-2 hours) exposure to a type of human coronavirus (HCoV-OC43), protected animals from infection suggesting that EK1C4 has prophylactic and/or therapeutic effects although within a limited time after infection, possibly resulting from deposition of HCoV-OC43 in the brain tissue. The authors conclude that since SARS-CoV2 infection mainly affects human lung cells, EK1C4 has higher potential in the context of SARS-CoV2 infection and can be used to develop the first intranasally administered antiviral drug for the prevention and/or treatment of SARS-CoV2 and future coronavirus infections.

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