| Further Information: | COVID-19 is an infectious disease caused by SARS-CoV-2, a new member of the same coronavirus family that caused SARS and MERS. It was found that the SARS-CoV-2 spike glycoprotein harbors a furin/PC cleavage site at the boundary between the S1/S2 subunits, which could be cleaved by furin and/or furin-like PCs secreted from host cells and bacteria in the airway epithelium [1, 2]. Unlike SARS-CoV, cell entry of SARS-CoV-2 is pre-activated by furin and/or furin-like PCs, reducing its dependence on target cell proteases for entry [3]. The cleavage activation of S-protein is well demonstrated to be essential for SARS-CoV-2 spike-mediated viral binding to ACE2, cell-cell fusion, and viral entry into human lung cells [4, 5]. It was also observed that other viruses containing a furin/PC cleavage site, such as H5N1, increased replicates and developed higher pathogenicity [6]. The SARS-CoV-2 furin/PC cleavage site has been with one core region SPRRAR?SV (eight amino acids, P6�P2?). The core region is very unique, as its P2 or P3 position is a positively charged residue (Arg), and another residue is hydrophobic (Ala). These factors allow this site to be cleaved by furin or furin-like PC and the cleavage efficiency to be facilitated by other serine proteases targeting dibasic amino acid sites such as matriptase, plasmin, human airway trypsin (HAT), and TMPRSS2. Furthermore, a serine at P6 could also highly increase the cleavage efficiency, causing increased viral replication, unrestricted organ tropism, virulence, and mortality rate as proven in H5N1 infection in mice [7]. The importance of measuring SARS-CoV-2S1/S2 site targeted cleavage PC or facilitating protease activity is emphasized by that the PC-based SARS-CoV-2 S1/S2 cleavage increases SARS-Cov-2 entry into cells and replication and eventually develops higher pathogenicity of COVID-19. |
