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Synthesis and Immunological Profiling of Mycobacterial Phenolic Glycolipids Analogs

  • Author / Creator
    Elsaidi, Hassan Ragab Hassan
  • 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.

  • Subjects / Keywords
  • Graduation date
    2012-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3JD4PX96
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Dr. Todd L. Lowary, Department of Chemistry
  • Examining committee members and their departments
    • Guo, Zhongwu (Department of Chemistry)
    • Cairo, Christopher W. (Department of Chemistry)
    • Campbell, Robert E. (Department of Chemistry)
    • Barreda, Daniel R. (Biological Sciences)
    • Brown, Alexander (Department of Chemistry)