Sulfoglycodendron\nAntivirals with Scalable Architectures\nand Activities

Many viruses initiate their cell-entry\nby binding their\nmultisubunit\nreceptors to human heparan sulfate proteoglycans (HSPG) and other\nmolecular components present on cellular membranes. These viral interactions\ncould be blocked and the whole viruses could be eliminated by suitable\nHSPG-mimetics providing multivalent binding to viral protein receptors.\nHere, large sulfoglycodendron HSPG-mimetics of different topologies,\nstructures, and sizes were designed to this purpose. Atomistic molecular\ndynamics simulations were used to examine the ability of these broad-spectrum\nantivirals to block multiprotein HSPG-receptors in HIV, SARS-CoV-2,\nHPV, and dengue viruses. To characterize the inhibitory potential\nof these mimetics, their binding to individual and multiple protein\nreceptors was examined. In particular, vectorial distributions of\nbinding energies between the mimetics and viral protein receptors\nwere introduced and calculated along the simulated trajectories. Space-dependent\nresidual analysis of the mimetic-receptor binding was also performed.\nThis analysis revealed the detailed nature of binding between these\nantivirals and viral protein receptors and provided evidence that\nlarge inhibitors with multivalent binding might act like a molecular\nglue initiating the self-assembly of protein receptors in enveloped\nviruses.