All animals except sponges produce mucus. Across the animal kingdom, this hydrogel mediates surface wetting, viscosity, and protection against microbes. The primary components of mucus hydrogels are mucinshigh molecular weight O-glycoproteins that adopt extended linear structures. Glycosylation is integral to mucin function, but other characteristics that give rise to their advantageous biological activities are unknown. We postulated that the extended conformation of mucins is critical for their ability to block microbial virulence phenotypes. To test this hypothesis, we developed synthetic mucin mimics that recapitulate the dense display of glycans and morphology of mucin. We varied the catalyst in a ring-opening metathesis polymerization (ROMP) to generate substituted norbornene-derived glycopolymers containing either cis- or trans-alkenes. Conformational analysis of the polymers based on allylic strain suggested that cis- rather than trans-poly­(norbornene) glycopolymers would adopt linear structures that mimic mucins. High-resolution atomic force micrographs of our polymers and natively purified Muc2, Muc5AC, and Muc5B mucins revealed that cis-polymers adopt extended, mucin-like structures. The cis-polymers retained this structure in solution and were more water-soluble than their trans-analogs. Consistent with mucin’s linear morphology, cis-glycopolymers were more potent binders of a bacterial virulence factor, cholera toxin. Our findings highlight the importance of the polymer backbone in mucin surrogate design and underscore the significance of the extended mucin backbone for inhibiting virulence.

Degradable polymers promote sustainability, mitigate environmental impact, and facilitate biological applications. Tailoring degradable polymers is challenging because installing functional group-rich side chains is difficult when the backbone itself is susceptible to degradation. A convenient means of side chain installation is through post-polymerization modification (PPM). In functionalizing polyoxazinones, a class of degradable polymers generated by the ring-opening metathesis polymerization (ROMP), we predictably found PPM challenging. Even the versatile azide-alkyne cycloaddition click reaction was ineffective. To solve this problem, we screened PPM reactions whose efficiencies could be assessed using photochemistry (excimer formation). The mildest, pH-neutral process was functionalization of a ketone-containing polymer to yield either oxime (acid labile)-or alkyoxylamine (stable)-substituted polymers. Using this approach, we equipped polymers with fluorophores, reporter groups, and bioactive epitopes. These modifications imbued the polymers with distinctive spectral properties and biological activities. Thus, polyoxazinones are now tunable through a modular method to diversify a macromolecule's function