LAUSR

Currently, the coronavirus disease 2019 (COVID-19) pandemic has become a serious concern to the worldwide healthcare system. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 and the emergence of new SARS-CoV-2 variants such as Omicron with higher potency for spread and infectivity, as well as immune scape characteristics toward vaccines can encourage us to provide new therapeutic insights for this disease. Recently, in a study, we described Ephrin (Eph) receptors as a possible SARS-CoV-2 entry receptor for human host cells in the central nervous system (CNS) and the potential roles of SARS-CoV-2 spike protein in stimulating the Eph receptor downstream signaling pathway for COVID19-associated neurodegenerative diseases [1]. In addition, studies have shown that Eph receptors express in a variety of tissues and organs such as the lung, liver, colon, small intestine, prostate, kidney, heart, etc. [2]. Thus, their cells could be potential host cells for SARS-CoV-2 to enter and/ or stimulate downstream signaling pathways. The SARS-CoV-2 receptor-binding motif (RBM) was discovered in another study by Beaudoin. Ch et al. to mimic ephrin-A5 and ephrin-B2 that bind to the ephrin type 4a receptor (EphA4). Accordingly, docking data indicated similar affinity values between the SARS-CoV-2 RBM–EphA4, ephrin-A5–EphA4, and experimental (PDB: 4m4r) complexes of -1.41, -3.32, and -0.45 kJ/mol, respectively [3]. In addition, researchers discovered that EphA2 promotes the intracellular fusion and internalization of Epstein–Barr Virus (EBV) by interacting with its encoded proteins gH/gL and gB, and the Ephrin ligand-binding domain and Ephrin fibronectin domain are necessary for EphA2-mediated EBV infection. Based on these results, EphA2 is necessary for EBV entry into epithelial cells. Furthermore, EphA2 may act as a co-receptors for hepatitis C virus (HCV) entry and tyrosine kinase inhibitors appear to have significant antiviral properties. The Eph receptor pathway is nearly entirely responsible for Ross River virus (RRV) entry into B cells and endothelial cells, whereas the Eph receptor is not necessary for RRV entry into fibroblasts and epithelial cells [4]. Here, we discussed other possible signaling pathways of Eph receptors that could be stimulated by SARS-CoV-2 spike protein in other diseases (especially cancer progression) as potential promising targeted therapy (Fig. 1). There are six parts to Eph receptors (Ephs): a ligandbinding domain (LBD), a cysteine-rich region (Cys), two fibronectin III repeats (FNIII), a transmembrane region (TM), a juxtamembrane region (JM), a tyrosine kinase domain (TK), and a PSD95/DLG/ZO-1 subunit. Ephrin-A stimulates activation of FYN and ERK and directly stimulates Src and RHOA through focal adhesion kinase (FAK). It can activate JAK2 by signal transducer and activator of transcription 3 (STAT3). It is known that EphA2 activates AKT in pancreatic cancer cells. Ephrin-Bs promotes endothelial-mesenchymal transition (EMT) and invasion by * Mohsen Nabi-Afjadi [email protected]