Chemical Synthesis of Biologically Significant Polysaccharides via LivingPolymerization - Chemical Synthesis of Biologically Significant Polysaccharides via Living Polymerization Polysaccharides are ubiquitous in biology and play indispensable roles in a variety of biological processes, such as energy storage and utilization, structural support and protection of cells, lubrication, signal transduction, and immune modulation. Owing to these crucial bioactivities, polysaccharides are a promising class of biomaterials. Polysaccharides extracted from natural sources are often highly heterogeneous and structurally complex, creating a significant barrier for establishing an understanding of structure-function relationships of polysaccharides and their utilization in various applications. While recent advances in stepwise glycan assembly techniques have enabled researchers to access chemically defined complex glycans, these procedures are often labor-intensive, resource-demanding, and scale-limited. In this proposal, we aim to develop a chemical synthesis platform for the facile and scalable synthesis of a variety of biologically significant polysaccharides via living cationic ring-opening polymerization. These polysaccharides include linear and branched glucan, mannan, arabinan, arabinomannan, poly-N-acetylglucosamine, and polyglucuronic acid. Our published prior works have shown that scalable synthesis of polysaccharides that possess native monosaccharide repeating units and glycosidic linkages, precisely controlled molecular weight, dispersity, chain-end groups, and chain architectures can be facilely achieved via living polymerization (Nat. Chem. 2023, 15, 1276-1284; J. Am. Chem. Soc. 2024, 146, 7963-7970). These promising results provided strong support to the feasibility of this project, allowing us to pursue all three of its distinct aims. In Aim 1, we will probe the mechanistic features of the living cationic ring- opening polymerization of 1,6-anhydrosugars and conduct mechanism-guided development of reaction conditions (e.g., catalysts, co-catalysts, chain transfer agents, etc.) toward enhanced reactivities and stereospecificity. In Aim 2, we develop substrate-controlled living cationic ring-opening polymerization to generate a variety of biologically significant polysaccharides with stereospecific glycosidic linkages, well- controlled molecular weights, and defined chain-end groups. In Aim 3, we will demonstrate the utility of the polysaccharides generated from living polymerization as immune modulatory biomaterials. We will investigate the receptor-dependent uptake of the polysaccharide-conjugated nanocarriers and the selective activation of immune cells derived from human primary monocytes. Taken together, the proposed research aims to greatly expand the toolkit for the chemical synthesis of polysaccharides and empower researchers to access tailor-made polysaccharides in sufficient scales for applications in biomaterials science and immune engineering.
