UC San Diego

The mucosal glycocalyx dictates cellular interactions with extracellular factors by providing a physical protective barrier around the host cell. This barrier, due to its heterogenous structure and prevalent non-templated glycosylation, is difficult to study through traditional biochemical means. Of particular challenge is the subclass of cell surface glycoconjugates known as mucins, which impart physiological function through their glycans and cytosolic signaling components but are also unique due to their massive size and extended architecture. The steric and exclusionary roles this enables are poorly understood due to a lack of chemical and biological tools with which to study these types of non-interacting “spectator” interactions. Especially relevant in light of the current COVID-19 pandemic are interactions between viral and epithelial surfaces mediated by the host’s defensive mucosal barrier. Though much attention has been paid to the viral subversion of innate defenses and co-opting of native sialyl receptors to aid infection, the role of the physical structure and bulk of mucins at the cellular interface is largely unexplored. In this thesis, I will describe the synthesis of PEG-based glycopolymers, appended with a diversity of pendant glycan moieties that approximate the structural roles of mucins, as a chemical biology tool to enable precise molecular control of these physical cell surface properties. Through incorporation onto red blood cells (RBCs), these glycopolymers generated an artificial mucosal barrier model system that reduced the association of multivalent lectins (SNA, ConA) with their underlying cell surface glycan receptors, and hinted at differences in how glycan binding proteins that target disparate regions of the glycocalyx are impacted by steric crowding. Next, I will show that increasing the density and extension of this artificial barrier reduced the association of both SNA and Influenza A virus to the cell surface, but counterintuitively led to enhanced receptor-ligand stability by inducing formation of high avidity Velcro-like patches. This approach provided new insights into the role of membrane anchored mucins in infection, and a new example of viral mechanisms to overcome host defenses. Finally, I will discuss the development of complementary sidechain modification chemistries to append larger and more complex glycans to these glycopolymers in an effort to further expand their functional utility.