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The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

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Abstract

In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.
... S protein remains inactive in its native state and during infection, it gets activated with the help of proteases of the host cell membrane using a transmembrane protease serine 2 (TMPRSS2) as a primer [9]. Upon receptor recognition, the host proteases cleave S protein into its subunits S1 and S2 at a furin-cleavage site [17]. S1 subunit is responsible for host cell receptor recognition, receptor interactions and binding, while the S2 domain brings about viral and host cell membrane fusion and viral entry into the host. ...
... The movements either expose or hide the receptor-binding regions and are termed as 'up' (receptor accessible) or 'down' (receptor inaccessible) conformations. RBD binding to cell surface receptor ACE2 prompts S1 to dissociate from ACE2 and this sets the stage for S2 to come into action for membrane fusion [17]. The function of the S1 subunit is to mediate receptor recognition and viral binding to the host membrane. ...
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... This cleavage site, absent in other coronaviruses, mimics the furin cleavable peptide on the epithelial sodium channel α-subunit (ENaC-α). Thus SARS-CoV-2 activates the ENaC-α causing cellular electrolyte imbalance responsible for fluid accumulation in COVID-19 patients (Anand et al., 2020;Coutard et al., 2020). ...
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... Besides, studies have shown that SARS-CoV-2 spike protein has 10-20 times more affinity than the same protein in SARS-CoV [23]. Following ACE2 receptor and ligand (here spike protein) binding, structural modifications are made in the spike protein that lead to the integration of the envelope protein with the host cell membrane [24]. The virus's RNA is then translated into the replica polyproteins pp1a and pp1b, which are further reduced to tiny proteins by virus-encoded proteinases. ...
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... After binding to ACE2, the spike protein of the virus is activated and cleaved by the cell TMPRSS2 and then the virus releases fusion peptides to enter cells (Shang et al., 2020). In addition, SARS-CoV-2 has its own furin cleavage sequence, which may enhance the affinity of the virus to host cells (Walls et al., 2020;Coutard et al., 2020). Previous studies showed that infection with SARS-CoV and MERS-CoV can cause kidney injury. ...
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... One important reason for this is the presence of four amino acid residues, P-R-R-A and R-S-V-R, at the S1/S2 junction in SARS-CoV-2 and MERS-CoV, respectively. This insertion generates a polybasic cleavage site, which enables effective cleavage by furin, a ubiquitously expressed membrane-bound protease, during spike biosynthesis [55][56][57][58][59]. Furin activation of SARS-CoV-2 S at the S2′ position has also been observed, but with less efficiency than that at the S1/S2 site [53]. ...
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