Introduction: In late ۲۰۱۹, an acute respiratory disease known as SARS-CoV-۲ (COVID-۱۹), caused by a novel coronavirus, emerged in Wuhan, China. This disease spread rapidly across China and globally. Many countries were compelled to develop and manufacture vaccines, antigens, diagnostic kits, and antiviral medications to mitigate mortality rates. Severe acute respiratory syndrome coronavirus۲ (SARS-CoV۲ or COVID-۱۹) uses its spike (S) protein to enable the virus to enter host cells. The viral entry process is linked to the cleavage of the spike (S) protein at the S۱| S۲ site. This cleavage can take place either at the plasma membrane of the host cell (known as the early pathway) or within the endosomal membrane (referred to as the late pathway), which is determined by the type of host cell involved. Previous research has identified a unique insertion in the S۲ region of COVID-۱۹, which may enhance the virus’s ability to target cells that express the appropriate proteases and receptors.Materials & Methods: ۳D models of the SARS-CoV and SARS-CoV۲ (or COVID-۱۹) spike-proteins (S-protein) were constructed, analyzed, and evaluated using the SARS-CoV spike-structure (PDB No.۵X۵۸) as a reference. The structure of CoVs models was reviewed using the online Cn۳D V۴.۳.۱ software. Additionally, CoVs sequences were analyzed utilizing the PiTou V۳.۰.۲ software.Results: Bioinformatics simulation results indicated that the majority of structural mutations enhancing the efficiency and activity of the S۲ subunit were located at the cleavage site (CVs) within the C-terminal region spanning from ۶۵۴ to ۶۹۱. Utilizing bioinformatics tools, an analysis of mutations was conducted within the S۲ subunit at the excision site and C-terminal region in related CoVs. Additionally, it provided insights into the origin of mutations such as furin and CVs in COVID-۱۹, and compared them with other CoVs.Conclusion: Most of the mutations that increase the aggressiveness of the S۲ subunit were observed in the S۲ C-terminal and CVs. Research has shown that furin and some other proteases are involved in processing these mutations. Among these, the transmembrane serine protease ۲ (TMPRSS۲) is crucial in enabling viral entry through the early pathway.
