Abstract
The ongoing pandemic illustrates limited therapeutic options for controlling SARS-CoV-2 infections, calling a need for additional therapeutic targets. The viral spike S glycoprotein binds to the human receptor angiotensin-converting enzyme 2 (ACE2) and then is activated by the host proteases. Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.
Highlights
Over the last 2 decades, several outbreaks of coronaviruses (CoVs) have received worldwide attention since they were responsible for the SARS in China (2002–2003) and the MERS-CoV (Middle East respiratory syndrome) in Saudi Arabia (2012)
Unique landscapes of SARS-CoV-2 entry are low frequency of receptor-binding domain (RBD) standing up that is implicated for immune evasion; its RBD has a high binding affinity to hACE2 that provides an efficient entry
Among different host factors that are involved in the entrance of SARS-CoV-2, transcriptional inhibition of the TMPRSS2 seems to be a hopeful strategy
Summary
Over the last 2 decades, several outbreaks of coronaviruses (CoVs) have received worldwide attention since they were responsible for the SARS (severe acute respiratory syndrome coronavirus) in China (2002–2003) and the MERS-CoV (Middle East respiratory syndrome) in Saudi Arabia (2012). Based on the accessibility of cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by two distinct ways; 1) by endocytosis and the cutting of the SARS-COV-2-S by cathepsin L in endosomes (Glowacka et al, 2011; Shirato et al, 2013) and 2) by TMPRSS2 provided that it is co-expressed with ACE2 on the target cells’ surface (Heurich et al, 2014) This binding process entails several conformational alternations in the viral envelope glycoproteins (Shen et al, 2017), resulting in virion internalization. The SARS-CoV-2’s spike protein has cleavage sites for the host cell proteases guaranteeing the exposure of the fusion sequences and viral entry. The role of cathepsin L is highlighted in virion entry into human embryonic kidney 293 cells expressing ACE2; CA-074 did not significantly affect SARS-CoV-2 entry (Pišlar et al, 2020)
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