The S protein consists of ∼1300 aminoacids and it is composed by a N-terminal “S1”subunit (∼700 aa) and a C-terminal “S2”subunit (∼600 aa); binding to the host receptor is mediated by S1, whereas S2 induces fusion of the viral envelope with cellular membranes (Walls et al., 2017). S1 and S2 can be further subdivided in functional segments with different roles in viral entry (Figure 4B; Tang et al., 2020). The S1 subunit contains two subdomains, the N-terminal domain (NTD) and the C-terminal domain (CTD). In SARS-CoV (Li, 2015) and SARS-CoV-2 (Wang et al., 2020) CTD encloses the receptor-binding domain (RBD), and the RBD section that directly contacts the receptor is named as receptor-binding motif (RBM). The N-region of S2 contains a fusion peptide (FP), two heptapeptide repeat domains (HR1, HR2), a transmembrane domain (TM), and cytoplasmic peptide (CP). FP is a short segment composed of mostly hydrophobic residues, such as glycine (G) or alanine (A), which inserts in the host cell membrane to trigger the fusion event. HR1 and HR2 are composed of a repetitive heptapeptide with HPPHCPC sequence, where H represents hydrophobic or bulky residues, P polar or hydrophilic residues, and C charged residues. HR regions typically fold into α-helices with a hydrophobic interface that drives membrane fusion.