Highly branched sulfated glycopolymers as mucin mimetics

Abstract

Mucins are highly complex glycoproteins that form protective and lubricating barriers around epithelial surfaces, e.g., in the respiratory tract, to protect against pathogens. The isolation and purification of natural mucins without compromising their structure and thus their properties remain challenging. Glycopolymers as mucin mimetics have shown great potential in biomedical research, for example, in mucosal barrier enhancement and respiratory disease treatment, or in improving surface lubrication and adhesion properties. Here, we introduce double-brushed mucin mimetic glycopolymers, replicating for the first time a structural design that more closely imitates key architectural features of natural mucins. By combining solid-phase synthesis of sequence-defined glycooligomers and their attachment onto polyactive ester scaffolds, we enable access to a library of linear, brushed, and double-brushed glycopolymers with controlled variations of structural parameters, such as overall chain length, number, and length of branches, as well as number of carbohydrates and degree of sulfation. By using light and neutron scattering as well as atomic force microscopy-based single-molecule force spectroscopy and imaging, we can demonstrate that the double-brushed architecture is responsible for successfully mimicking critical mucin properties, such as their adhesion to hydrophilic surfaces and an extended conformation, properties that are not achieved with single-brushed or linear analogues. Thus, our findings show that double-brushed sulfated glycopolymers effectively replicate key characteristics of natural mucins, advancing their potential as mucin models, as well as for use in biomedical applications.