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Synthesis and Immunological Profiling of Mycobacterial Phenolic Glycolipids Analogs Open Access


Other title
cell wall
phenolic glycolipids
Type of item
Degree grantor
University of Alberta
Author or creator
Elsaidi, Hassan Ragab Hassan
Supervisor and department
Dr. Todd L. Lowary, Department of Chemistry
Examining committee member and department
Guo, Zhongwu (Department of Chemistry)
Cairo, Christopher W. (Department of Chemistry)
Brown, Alexander (Department of Chemistry)
Campbell, Robert E. (Department of Chemistry)
Barreda, Daniel R. (Biological Sciences)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Mycobacterium tuberculosis, M. leprae and M. kansasii are three members of the mycobacteria family that cause serious bacterial infections in humans. Another member of the mycobacteria family is M. bovis that affects a range of animals, mainly cattle, and humans. These four bacteria share a common characteristic, which is a complex cell wall that is important for survival of the bacteria, virulence and pathogenesis. Of particular interest to this project is a family of non-covalently bound cell surface antigens known as phenolic glycolipids (PGLs). Despite all the work done on PGLs from Mtb and M. leprae, their immunological profile is yet to be determined. In order to achieve this goal, a panel of all PGLs from the four mycobacteria is needed. The difficulty of getting these molecules from the bacteria made their chemical synthesis crucial. To this end, a panel of 27 synthetic analogs to all PGLs was synthesized with p-methoxyphenyl group at the reducing end. With these compounds in hand, they were tested for their ability to modulate cytokine as well as nitric oxide release by human macrophages. The results revealed PGLs have immunoinhibitory activity on the release of IL-6, TNF-α, IL-1β, MCP-1 and NO. The inhibition pattern was the same as the native PGL-I and is related to the polymethylation pattern of the molecule. In addition, all monosaccharides were inactive and disaccharide structure was the minimum needed to have activity. Furthermore, adding a simple lipid core increased the activity, but not to the level of the native PGLs. This suggested that the native lipid core is needed for the receptor recognition. To extend the scope of this study, different cell stimulants were used, LPS (TLR2/4 agonist), ultra pure LPS (TLR4 agonist) and Pam3CSK4 (TLR2 agonist) were used. The results of this testing suggested that these analogs are targeting TLR2 and not TLR4 as the immunoinhibitory pattern of these molecules were maintained upon using LPS and Pam3CSK4 as a stimulant. However, no effect was obtained when ultra pure LPS was used. Finally, when these molecules were tested for apoptosis, none of them showed any activity to induce apoptosis.
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