Fig. 1.

Mechanism of SARS-CoV-2 cell entry. (A) Non-endosomal Pathway. SARS- CoV-2 upon contact with host cell surface, spike protein (SP) projecting from the viral cell surface, first undergoes proteolytic cleavage by TMPRSS2 and exposes its receptor binding domain (RBD) and attaches to the ACE-2 receptor on host cell surface via SP. TMPRSS2 also cleaves ACE-2 along with ADAM17 because of which shedding of ACE-2 ectodomain occurs which can still bind to virus. After its attachment, virus fuses with host cell and releases its genome. Viral RNA undergoes transcription, translation and form new viral particles, new viral particles then release from host cell. TMPRSS2 inhibitors may inhibit TMPRSS and thereby exposure of RBD to ACE-2. (B) Endosomal Pathway. SARS-CoV-2 upon contact with host cell surface, signals the host cell and forms a vesicle enclosing virus–ACE-2 complex. Then endocytosis of virus-ACE-2 complex occurs, into the host cell cytoplasm followed by H⁺ influx into endosome. Decreased pH in endosome activates Cathepsin L, which cleaves SP of virus. Then virus fuses with endosomal membrane and releases its genome. Viral genome transcribes and translates into viral particles, viral particles fuse and release out of host cell. Cathepsin L inhibitors may inhibit Cathepsin L cleavage of viral SP.