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.

The 2nd major reason for the novelty behind the discovery of SPGG is the possibility of simultaneous engagement of multiple receptors involved in HCMV entry into host cells. Complex interactions between viral envelope glycoproteins and host cell receptors come into play for successful entry [23, 24] . One reason why nature seems to have engineered multiplicity of such interactions is to ensure probability of success. To significantly reduce efficiency of entry, it is important to simultaneously impact these interactions. Thus, targeting only interactions of 3-O-sulfated or 6-O-sulfated species, inhibition of HCMV entry may not yield a clinically viable agent. Despite being small, SPGG presents a diverse library of sulfated species that could bind all possible heparan sulfate binding receptors, thereby impeding viral recognition. This appears to be the case because SPGG binding to glycoprotein gB explains only part of the inhibition effect. Thus, pleiotropicity of SPGG interactions may be a key reason for its high anti-HCMV potency.