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Abstract_Dr. Rachel HEVEY_The importance of mucin glycans in the design of mucus-mimicking artificial biopolymers
Glycans (i.e., carbohydrates) are an important family of natural products which coat all cell surfaces and play essential roles in cell signaling and function. Many diseases are characterized by changes in glycan composition, highlighting glycans as both critical biological regulators and suggesting their potential utility as therapeutic targets.
The mucosal barrier is well-established to play an important role in microbiome development and as a first line of host defense. Although this has traditionally been attributed to the bulk physicochemical properties of mucin glycoproteins (the main protein component of mucus), several recent publications from us and others indicate that specific glycan structures displayed on mucins can regulate gene expression and are capable of attenuating virulence in diverse, cross-kingdom pathogens (Gram-negative bacteria, Gram-positive bacteria, and fungi). These findings reveal that glycans on mucins are not passive structural elements, but dynamic bioactive signals responsible for modulating biological behavior across kingdoms. Therefore, glycan motifs become an important consideration in the design of next-generation mucus-mimicking artificial biopolymers.
However, mucins present several hundred distinct glycan structures, and dissecting their individual contributions remains a major challenge due to limited access to pure glycans. To address this, we have established a multidisciplinary and multi-institutional platform that integrates: (i) advanced analytical characterization of complex mucin glycan pools to identify potentially bioactive structures; (ii) integrated (bio)synthetic strategies to generate individual mucin glycans in sufficient quantities for functional analysis; and (iii) assessing the virulence attenuating capabilities of individual mucin glycans and their associated anti-virulence mechanisms.
Within this framework, we have identified specific glycan structures that can recapitulate the virulence-attenuating activity of native mucin glycan mixtures with comparable potency. Importantly, the incorporation of these glycans onto synthetic polymer backbones will enable the development of biomaterials that better mimic mucosal interfaces and can actively modulate microbial behavior. These findings establish glycans as a critical design parameter in bioinspired polymer systems and open new avenues for the development of anti-virulence materials, infection-resistant coatings, and microbiome-informed therapeutics.