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.