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Figure 1. (Adapted from Ref. 1) The left panel is a cartoon of S-protein showing S1-cleavage site-S2 protein. The right panel is the Fig. 5 of the paper: A working model for SARS-CoV-2-induced lymphocyte internalization (orange cells at the far right) and syncytia giant cell formation. Infection by SARS-CoV-2 virus via ACE-2 receptors leads to the surface expression of viral S-protein. S-protein will bind neighboring cells’ ACE2 receptor and trigger membrane fusion, leading to the production of multinucleated giant cells, the syncytia. The syncytia are capable of targeting lymphocytes for internalization, contributing to lymphopenia in COVID-19 patients with reduced innate immunity.
An article (Ref 1) just published on one of Nature series- Cell Death and Differentiation was found to be relevant to possible antidotes for SARS-CoV-2. The authors are affiliated with the Chinese Academy of Medical Science (corresponding author: Qiang Sun) and several military institutions of the People’s Republic of China.
This paper shed important information on the mechanism of a commonly observed phenomenon, heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytial cells, in autopsy lung tissue after SARS-CoV-2 infection. The authors found that the expression of the S-protein is sufficient to induce a rapid membrane fusion with neighboring cells to produce multinucleated giant cells that can internalize and ‘eliminate’ lymphocytes, contributing to lymphocyte loss in patients with COVID-19.
More importantly, this fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which was the artificial lab-engineered unique “furin-cleavage site” (PRRA residual) that Dr. Yan’s first report has revealed (https://zenodo.org/record/4028830#.YI3woKETGUl). This explains the irreversible respiratory cell damage and lymphocytopenia of infected patients. This “switch-on” element for membrane fusion was embedded into the S2-protein of SARS-CoV-2, that is the insertion of 4 amino acids (PRRA) before the S1/S2 cleavage site. This was supported by 2 pieces of evidence: 1. SARS-CoV-1 could not induce membrane fusion due to the lack of such region; and 2. if the region was removed by genetic modification or inhibited by inhibitors, the membrane fusion will be inhibited.
“Some of the tested candidate anti-viral compounds, including 6-D-Arg, Con A, NH4Cl, Arbidol (Ref. 2), and hydroxychloroquine (HCQ), could efficiently inhibit S2 production and syncytium formation as well. The authors “unexpectedly identified” HCQ as a potent inhibitor for both cell fusion and internalization of lymphocytes, which “provides a molecular and cellular rationale for hydroxychloroquine treatment of COVID-19.” Other in silico studies (Ref. 3 & 4) have shown HCQ may directly interfere with the binding of S-protein to its ACE-2 receptors.
The authors also found that “Interestingly, a similar bi-arginine motif (RxxR), present in the SARS-CoV-2 S glycoprotein, was also identified in the pre-cleavage site of surface glycoproteins of other highly contagious viruses, such as the RSV, HIV, and H5N3 and H7N1 flu viruses, but not in other species of flu viruses that are less contagious such as H1N1.” So, is this the site that the CCP inserted to increase its transmissibility? The authors even proposed to “transplanting the pre-cleavage motif of H7N1 surface glycoprotein into the SARS-CoV-2 S glycoprotein could also mediate S2 production and syncytium formation, as opposed to the low contagious H1N1 virus motif.” Is this another example of ‘gain-of-function” study?
On another note, there was a patent application submitted by George Gao, Fu Gao, the University of Wuhan, and the Chinese Academy of Science (Microbiology) in May 2003 and granted in October 2005 (Patent #Zl03136220.6). The patent is for a polypeptide and derivatives serving as an inhibitor for SARS-CoV infection. The inhibitor is based on two heptapeptide repeats HR1 and HR2 (see Fig. 1) on the S2 protein of coronavirus. They claimed that HR1/2 are widespread in coronaviruses. This is also where the furin-cleavage site locates. It also claimed that derivatives with substitutions, insertions, or deletions of amino acids in peptides are still valid.
The researchers should screen for chemicals or drugs that can have inhibition effects on this region as suggested by the paper (Ref. 1). This might shed light on the dark days that the pandemic has brought to us.
1. Zhang, Z., Zheng, Y., Niu, Z. et al. SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination. Cell Death Differ (2021). https://www.nature.com/articles/s41418-021-00782-3
2. Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ. Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr Med Chem. 2008;15(10):997-1005. doi: 10.2174/092986708784049658. PMID: 18393857. https://pubmed.ncbi.nlm.nih.gov/18393857/
3. Fantini J, Di Scala C, Chahinian H, Yahi N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55:105960. Download PDF.
4. Amin M, Abbas G. Docking study of Chloroquine and Hydroxychloroquine interaction with SARS-CoV-2 spike glycoprotein-An in silico insight into the comparative efficacy of repurposing antiviral drugs. J Biomol Struct Dyn. 2020; https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1775703.
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