MERS-CoV S glycoprotein also recognizes a 78-kDa glucose–regulated protein (GRP78) or heat shock 70 kDa protein 5 (HSPA5), known as binding immunoglobulin protein (BiP) or Byun1, which is encoded by the HSPA5 gene in humans. HSP5A is a ER-resident unfolded protein response (UPR) protein. Stressed cell status such as viral infection increase expression and translocation of HSPA5 to the PM to form a membrane protein complex. GRP78 modulates MERS-CoV entry in the presence of the DPP4 as a host cell receptor. Additionally, lineage D β-CoV and bat CoV HKU9 (bCoV-HKU9) also bind to GRP78 [76]. A cell surface receptor, GRP78, was predicted to be another COVID-19 receptor as an S glycoprotein binding site [110]. The prediction was made using the combined technology of molecular modeling docking with structural bioinformatics. GRP78 or BiP is a chaperone protein located in the ER lumen [111]. Known ER-bound enzymes include activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1) and protein kinase RNA (PKR)-like ER kinase (PERK) [112]. Depending on threshold of unfolded protein accumulation, GRP78 releases IRE1, ATF6 and PERK, and is activated, resulting in translation inhibition and refolding. Stress-overexpressed GRP78 can avoid ER retention and is translocated to the membrane. GRP78 translocated to the cell PM can recognize viruses by its substrate-binding domain (SBD) for virus entry into the cell (Figure 8). In sequence and structural alignments and protein–protein docking, RBD of the CoV spike protein recognizes the GRP78 SBDβ as the host cell receptor. The predicted region III (C391–C525) and region IV (C480–C488) of the S glycoprotein and GRP78 are highly potential binding sites. Region IV is the GRP78 binding-driving force. These nine amino acid residues are being molecularly targeted for the designation and simulation of COVID-19-specific drugs. This process is the mechanism underlying the cell surface HSPA5 (GRP78) exposure and this is exploited to be used for pathogen entry. Such pathogenic entry into host cells has been observed in multiple infections including pathogenic human viruses such as human papillomavirus, Ebola virus, Zika virus and HcoVs—as well as fungal Rhizopus oryzae [113,114,115,116]. Therefore, natural products can inhibit cell-surface HSPA5 recognition of the viral S glycoprotein.