UC San Diego

Glycans are one of the four major building blocks of life, along with nucleic acids, proteins, and lipids. These biomolecules are composed of monosaccharide sugar building blocks and are ubiquitously expressed by all animal, bacterial, and fungal cells. However, unlike RNA, DNA, and protein, the synthesis of this class of biomolecules is not directed by a template, making the study of glycans particularly cumbersome. Instead, each glycan’s abundance changes in response to many stimuli, such as availability of monosaccharide precursors, expression levels of enzymes required to elongate a glycan chain, and the amount of time a nascent glycan chain resides in the Golgi during synthesis and subsequent processing steps. There are approximately ten monosaccharides commonly found in human glycans that can be linked in a number of configurations to give hundreds, if not thousands, of unique structures within the glycome. Many of these glycans are attached to lipids or proteins as glycolipid or glycoprotein glycoconjugates that are presented above the cell surface in a forest of sugars known as the glycocalyx. The biological relevance of glycans is becoming increasingly apparent. Not only are simple sugars, such as glucose, an important source of fuel for the cell, the glycans displayed at the cell surface have known implications in immunity, disease, cell signaling, and differentiation. Influenza A virus (IAV) is a well-studied pathogen that binds to sialic acid-containing glycans to gain entry into cells and initiate infection. Sialic acid frequently terminates N-and O-linked glycans on glycoproteins, as well as glycolipids to allow for many interactions with IAV. Because of the intrinsic heterogeneity of glycans, the exact molecular features defining the presentation of this viral receptor within the glycocalyx remain unknown. While there have been substantial advancements in methods to probe IAV binding in recent years, many of the investigations fail to recapitulate key aspects of the glycocalyx, such as the multivalency of glycans along a protein backbone. The following thesis chapters, describe, in detail, work I have done to improve current synthetic platforms for systematic examination IAV adhesion and release from its sialic acid receptors, as well as, establishing a method to study viral binding within the cellular glycocalyx.