Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Elste, James; Kaltenbach, Dominik; Patel, Vraj R.; Nguyen, Max T.; Sharthiya, Harsh; Tandon, Ritesh; Mehta, Satish K.; Volin, Michael V.; Fornaro, Michele; Tiwari, Vaibhav; Desai, Umesh R.

HCMV entry into host cells is extremely dynamic due to the usage of a variety of cellular entry receptors during virus-cell interactions [21] [22] [23] [24] . It has been shown that depending on the cell type, HCMV can utilize multiple target cell receptors, including cell surface heparan sulfate (HS), different cellular integrins, platelet-derived growth factor receptor alpha (PDGF-Rα), neuropilin-2 and epidermal growth factor receptor (EGF-R), for cellular entry [25] [26] [27] [28] [29] [30] [31] . On the flip side, HCMV's multiple viral glycoproteins, including gB, gO, and gH-gL, engage these structurally and functionally unrelated receptors to penetrate cellular defenses. For example, gB catalyzes membrane fusion between HCMV and infected cells, while gH/gL-containing complexes regulate viral tropism [24] . Interestingly, these viral glycoproteins contribute differently to different cell-types. Whereas the trimer of HCMV's gH-gL-gO is critical for infection in fibroblasts, a pentamer unit of gHgLpUL128-131A is essential for viral entry in epithelial, endothelial, and myeloid cells [32] [33] [34] . The distinctive ability of HCMV to utilize a diversity of cell surface receptors coupled to its exploitation of multiple glycoproteins to mediate entry pose a special challenge for drug discovery because of the possibility of several bypass mechanisms.