FIGURE 5  Coronavirus viral fusion pathway model. Initially, the S protein is in the pre-fusion native state (1). Then S undergoes priming of the S1 subunit at S1/S2 by local proteases yielding the pre-fusion metastable state (2); note that priming at S1/S2 could also happen upon virus formation in releasing cell: in such a case the virus attaches to a host cell already in the pre-fusion metastable state (2). Subsequent triggering by a protease on S2’ enables the FP to insert in the host membrane upon the “jack-knife” transition of HR1 and HR2 yielding the pre-hairpin intermediate (3). The pre-hairpin folds back on itself due to HR1 and HR2 interactions eventually forming the post-fusion (6) state. During the S protein foldback, the two membranes approach each other until the outer leaflets merge (hemifusion) and eventually the inner leaflets merge (pore formation). Note that cell membrane may refer to plasma membrane (direct fusion) or endosomal membrane (fusion in endocytic vesicle). Adapted from Tang et al. (2020).