Self-assembled nanosheets of biocompatible polymers as universal cell-membrane mimic to block viral infection

Viruses cause severe damage to society due to seasonal and pandemic outbreaks; therefore, developing new antivirals is urgently needed. Multivalent virus inhibitors are promising broad-spectrum antivirals, as they can block the initial step of viral infection by mimicking the structure of the cell receptors on the host cell membrane. Biocompatible supramolecular architectures are particularly well-suited for virus inhibition due to the numerous weak non-covalent bindings, resulting in strong yet dynamic multivalent interactions. Herein, we report on supramolecular nanosheets based on dendritic polyglycerol (dPG). The dPG core was functionalized with different ratios of sulfate and mercaptoundecanoic acid (MUA) groups. The MUA, as the hydrophobic part, triggers the self-assembly and -via the acid group-the supramolecular interaction with the virus, while sulfate groups mimic heparan sulfate proteoglycans (HSPG) on the cell membrane for virus interaction. The effect of polymer functionalization degree of MUA (ranging from 30 to 100 %) on the nanosheet size and morphology, as well as their interaction with viral particles, were monitored by cryo-transmission electron microscopy (cryo-TEM) and cryo-electron tomography (cryo-ET). Bio-functional assays such as plaque reduction, pre-infection inhibition, hemagglutination inhibition (HAI) and cell viability assays have been performed to assess the in vitro efficiency of supramolecular nanosheets against Influenza A virus and Herpes-simplex virus type 1. These studies revealed inhibitory activities against IAV (X31/H3N2) and HSV-1 with the half-inhibitory concentration (IC₅₀) of 1 and 0.01 μg/mL in vitro, respectively, demonstrating its potential of being a universal virus inhibitor by dynamic multivalent interactions.