Thursday, April 25, 2024
4/25/2024
Abstract Sialylated glycans are widely distributed in mammalian tissues and participate in critical molecular recognition events that mediate diverse normal biological processes, and pathological processes including infectious diseases, cancer, autoimmune disease, allergies, Alzheimer’s disease, and many others. In the golgi apparatus, the 20 known sialyltransferases catalyze the attachment of sialic acid to the penultimate sugar via three different types of linkages (a2,3-, a2,6-, or a2,8-) to generate a great diversity of sialoglycoconjugates. The numerous biomedically relevant processes mediated by sialylated glycans are sialic acid linkage dependent. Thus, tools that can advance our knowledge of sialoglycoconjugate structure and function, and correlate changes with disease state are of great biomedical interest. Metabolic oligosaccharide engineering and sialyltransferase inhibition are two powerful approaches to manipulate the expression of cell surface sialoglycans. However, the current chemical tools used in these strategies are substrates for most sialyltransferases and therefore report on global sialylation. The goal of this project is to develop novel chemical tools to address the limitations of these current technologies. In Aim 1 we will develop sialyltransferase selective chemical tools for metabolic incorporation of sialic acid reporters in a linkage specific manner. These tools will allow detection, imaging, and purification of sialoglycoconjugates based on sialic acid linkage. In Aim 2 we will develop sialyltransferase selective inhibitors that will enable the inhibition of specific sialyltransferases and provide a means to explore the effects of blocking sialylation in a linkage specific manner. The selective tools will be initially developed by screening against a panel of recombinant human sialyltransferases then validated in cells. The tools developed in this project will find broad use in biomedical research as they can be readily adapted to any cellular system and provide more detailed information about specific sialylation in different disease states.
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