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.

This work demonstrates for the first time the concept that small synthetic sulfated agents could effectively inhibit HCMV entry into host cells. Although previous work has demonstrated the concept that certain sulfated, natural, or unnatural polysaccharides (e.g., dextran sulfate, pentosan polysulfate, heparin, copolymers of acrylic acid) can inhibit HCMV infectivity in CHO-K1 and MRC-5 cells [71] , the foundation for this activity was based on mimicking the polymeric scaffold of heparan sulfate, which has now been shown to be critical for HCMV entry [72] [73] [74] [75] . In fact, the plausible molecular basis for this competitive inhibition was the interaction of sulfated polymers to viral glycoprotein gB of HCMV [25] [26] [27] . More specifically, the competitive inhibition was predicted to arise from mimicking the structure of certain heparan sulfates, e.g., 3-O sulfated and 6-O sulfated species [74] . In stark contrast, SPGG is a much smaller sulfated entity that performs the mimicking function with excellent potency. This is important because a smaller molecular scaffold is easier to transform into clinical drug candidates. Whereas polymers are difficult to synthesize, characterize, purify, analyze, monitor, and administer, smaller molecules are the exact opposite. Thus, SPGG provides the first small molecule lead toward discovery of anti-HCMV drugs.