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Abstract
The importance of cellular oligosaccharides and glycoconjugates to critical biological processes such as bacterial and viral infection, leukocyte-endothelial cell adhesion, and immunological recognition of tumor cells, has made them attractive targets for synthetic medicinal chemists. Following microbial detection, over-activation of innate immune responses can lead to sepsis. The molecular basis for innate immune detection of bacterial cell wall peptidoglycan (PGN), a component of the cell wall of almost all bacteria, by the germline encoded innate immune cell expressed Toll-like receptor 2 (TLR2) is poorly understood. In this dissertation, it was demonstrated through surface plasmon resonance technology and cellular activation studies that TLR2 binds PGN fragments derived from both Gram- positive and -negative bacteria. Furthermore, the structural and functional significance of PGN partial structures were analyzed as potential indicator of bacterial endotoxicity. The established structure-activity relationships also demonstrated that host and pathogen can exploit structural differences between PGN of different bacterial strains to modulate or evade immune detection. Next, a glycoconjugate construct of Mannostatin A was analyzed for selective inhibition of golgi -mannosidase. Mannostatin A, originally isolated from the soil microorganism Streptoverticillus, is one of the most potent inhibitor of class II -mannosidase known to interfere in the biosynthesis of oligosaccharides critical in tumor progression and metastasis. Here, a feedback pro-drug inhibitor of mannostatin A (aminocylopentitetrol as control) was designed and screened for selective -mannosidase inhibition. Through in vitro and cell based studies, it was determined that the enzyme dependent fragmentation of the pro-drug results to increase local concentration around the enzyme resulting in selective inhibition of mannosidases.