Several proteins of human CoVs are important for viral infection and/or pathogenesis. For example, most nsps participate in viral RNA replication and/or transcription (Snijder et al., 2016). The accessory proteins interact with host cells, potentially helping the viruses to evade the immune system and increase their virulence (Menachery et al., 2017). The HE protein assists in the attachment of virus–host cells, thus playing a key role in the production of infectious virions, as in the case of HCoV-OC43 (Desforges et al., 2013). The M and E proteins are responsible for virus assembly or promote virulence (Scobey et al., 2013; DeDiego et al., 2014). Different from the above proteins, the S protein of human CoVs mediates viral entry into host cells and subsequent membrane fusion, enabling viral infection (Du et al., 2009a; Lu et al., 2014). The S protein is a class I viral protein, which can be cleaved into two functional subunits, an amino-terminal S1 subunit and a carboxyl-terminal S2 subunit. The S1 subunit is responsible for virus–host cell receptor binding, whereas the S2 subunit is involved in virus–host membrane fusion (Li et al., 2005a; Lu et al., 2014). The S1 contains two major domains, an N-terminal domain (NTD) and a C-terminal domain (CTD). In general, NTDs mediate sugar binding (Li, 2016; Li et al., 2017; Ou et al., 2017; Hulswit et al., 2019; Tortorici et al., 2019), whereas CTDs facilitate protein receptor recognition (Wong et al., 2004; Hofmann et al., 2006; Lu et al., 2013). The NTDs and CTDs of the S1 subunit can bind host receptors or function as receptor-binding domains (RBDs) (Lu et al., 2013; Hulswit et al., 2019). The entry of human CoVs relies on the interaction between viral and cellular membrane proteins. Recognition of S1 subunit with a receptor and/or sugar on the cell surface initiates the infection (Li, 2015). After the initial recognition and binding, the S protein undergoes conformational changes, followed by membrane fusion through the S2 region (Li, 2015, 2016; Du et al., 2017). Consequently, the viral genetic materials are delivered into the host cell through the fusion core (Du et al., 2009a).