Bioinspired Design and Synthesis of Bottlebrush Polymers to Mimic the Selective Antiviral Properties of Natural Mucins

The mucosal layer serves as the primary defense barrier protecting the underlying epithelial cells from pathogens.  The recognition mechanism is primarily governed by the specific interaction between sialic acid residues on mucin biopolymers and the hemagglutinin proteins on viruses.  While many previous studies have shown that enhanced binding is achieved through a multivalent effect, it remains unclear how the brush-like molecular architecture of mucins contributes to their biological function.

Here, we present our effort to address this open question by exploring the structure-property relationship in synthetic bottlebrush polymers with highly specific and strong antiviral properties comparable to natural mucins.  The synthetic analogs are prepared from polymerizing norbornyl macromonomers with sialyl N-linked oligosaccharides via ring opening metathesis polymerization (ROMP).  Our modular design allows precise control over the molecular architecture, including the molecular weight of the polymer backbone and sidechains, as well as the functionalization degree of the sugar moieties.  The antiviral properties of the synthetic brush polymers are evaluated by hemagglutination inhibition assays and infectivitiy assays, which show nearly comparable inhibition constant to natural mucins after optimizing the molecular determinants.  In addition, the synthetic polymers show highly selective recognition to different influenza A viruses, providing an opportunity to engineer biosensors that rapidly distinguish viruses and quantify their toxicity to human.  Studies on the synthetic mucin mimics will provide new insights into the complex structure-property relationship in other biomaterials.