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

Abstract

Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.

Discovering small-molecule therapeutics against SARS-CoV-2

“…4). This supports the expectation that heparin-like molecules, such as glycosaminoglycan mimetics, which have been found to potently inhibit HSV and HCMV [79,80], could also be good inhibitors of SARS-CoV-2.…”

Preferential recognition and antagonism of SARS-CoV-2 spike glycoprotein binding to 3-O-sulfated heparan sulfate

“…The highly sulfated nature of the HS hexasaccharides identified through computational studies ( Figures 2 and S6, Table S1), also led us to reason that a synthetic, small, non-sugar, highly sulfated compound, called SPGG, could serve as an effective inhibitor of cell-to-cell fusion mediated by SgP ( Figure 4 ). SPGG has recently been identified as a highly promising pan-virus antagonist of cellular entry because it competes for viral glycoproteins, such as glycoprotein D of HSV, that are involved in recognition of cell surface HSPGs ( 41 – 44 ). We studied SPGG’s effect on cell-to-cell fusion in CHO-K1 cells as well human HEK293T cells.…”

Antiviral T-Cell Frequencies in a Healthy Population: Reference Values for Evaluating Antiviral Immune Cell Profiles in Immunocompromised Patients

“…Although antiviral drug treatments have advanced over the years, they are still associated with toxic side effects. In the absence of functional VSTs, they can only control but not completely eliminate viruses [16,33,34]. Antiviral T-cell frequencies determine whether treatment (e.g., antiviral drug therapy, reduction of immunosuppression, or AT) is needed [35][36][37].…”

“…However, they are associated with toxic side effects and ineffective in case of drug resistances. Moreover, due to insufficient reconstitution of cellular immunity, viral infections can only be controlled but not completely eliminated [16,33,34]. A major clinical challenge remains the complex interplay between immunosuppressive treatment and the maintenance or establishment of antiviral immunity [8].…”