Fig. 1. Pathways of SARS-CoV-2 cell entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2; step 1 in the left and right panels) on the host-cell membrane and undergoes a conformational change in the spike protein subunit 1 (S1) leading to exposure of the S2′ cleavage site in the S2 subunit of the virus; these cleavage events in the two spike proteins of the virus are necessary for the virus entry process. Two viral entry pathways (endosomal and cell surface) are available. Left: in the case of insufficient transmembrane protease serine 2 (TMPRSS2) levels on the host cell, or if a virus–ACE2 complex does not encounter TMPRSS2, the virus–ACE2 complex is internalized via clathrin-mediated endocytosis (step 2) into the endolysosomal compartment, where S2′ is cleaved by the enzymes cathepsins, working in an acidic environment (steps 3 and 4). Right: in the presence of TMPRSS2, S2′ is cleaved at the cell surface (step 2). In both entry pathways, cleavage of the S2′ site exposes the fusion peptide (FP) and induces dissociation of S1 from S2. A dramatic conformational change in the S2 subunit moves the FP forward into the target membrane, initiating membrane fusion (step 5 on the left and step 3 on the right). After the fusion between viral and cellular membranes, viral RNA is released into the host-cell cytoplasm through a fusion pore and viral RNA uncoating occurs (step 6 on the left and step 4 on the right). Several agents disrupt the interaction between the S proteins and ACE2, such as ACE2 mimetics, therapeutic antibodies (targeting S protein) and vaccine-elicited antibodies (blocking the virus binding to ACE2). Other strategies target post-receptor-binding steps: the serine protease inhibitor camostat mesylate acts on TMPRSS2, blocking the TMPRSS2-mediated entry pathway; hydroxychloroquine and chloroquine block endosomal acidification, which is necessary for cathepsin activity, acting on the cathepsin-mediated entry pathway. Reprinted from ref.¹⁹, Springer Nature Limited.