No abstract

The entry process of viruses into host cells is complex and involves stable but transient multivalent interactions with different cell surface receptors. The initial contact of several viruses begins with attachment to heparan sulfate (HS) proteoglycans on the cell surface, which results in a cascade of events that end up with virus entry. The development of antiviral agents based on multivalent interactions to shield virus particles and block initial interactions with cellular receptors has attracted attention in antiviral research. Here, we designed nanogels with different degrees of flexibility based on dendritic polyglycerol sulfate to mimic cellular HS. The designed nanogels are nontoxic and broad-spectrum, can multivalently interact with viral glycoproteins, shield virus surfaces, and efficiently block infection. We also visualized virus-nanogel interactions as well as the uptake of nanogels by the cells through clathrin-mediated endocytosis using confocal microscopy. As many human viruses attach to the cells through HS moieties, we introduce our flexible nanogels as robust inhibitors for these viruses.

Carbon-based architectures, especially graphene and its derivatives, have recently attracted much attention in the field of biomedicine and biotechnology for their use as pathogen inhibitors or biosensors. One of the major problems in the development of novel virus inhibitor systems is the adaption of the inhibitor to the size of virus particles. We here report the synthesis and biological testing of carbon-based inhibitors differing in size for evaluating the potential size effect on the inhibition of virus entry and replication. In this context, different sized nanomaterials were functionalized with polygylcerol through a "grafting from" polymerization to form new polyvalent nanoarchitectures which can operate as viral inhibitor systems after post-modification. For this purpose a polysulfation was carried out to mimic the heparan sulfates present on cell surfaces that we reasoned would compete with the binding sites of herpes simplex virus type 1 (HSV-1) and equine herpesvirus type 1 (EHV-1), which both cause major global health issues. Our results clearly demonstrate that the inhibitory efficiency is regulated by the size of the polymeric nanomaterials and the degree of sulfation. The best inhibiting graphene sheets were ∼300 nm in size and had a degree of sulfation of ∼10%. Furthermore, it turned out that the derivatives inhibited virus infection at an early stage during entry but did not affect cell-to-cell spread. Overall, tunable polyvalent nanomaterials are promising and efficient virus entry inhibitors, which can likely be used for a broad spectrum of enveloped viruses.

Schematic representation of synergistic action of electrostatic interactions of polyglycerol sulfate and conjugated aliphatic chains to the surface of nG-PGS.