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The Design, Synthesis and Evaluation of Multivalent Heterobifunctional Ligands Specific for Shiga Toxin 1 and Shiga Toxin 2

  • Author / Creator
    Jacobson, Jared M
  • Hemolytic uremic syndrome (HUS) is a potential life-threatening condition caused by infection with Shiga toxin-producing Escherichia coli O157:H7. There are two major types of Shiga toxins, namely, Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), of which, Stx2 is clinically most closely associated with enterohemorrhagic E. coli O157:H7-mediated HUS. The ability to express the toxin has been acquired by other E. coli strains and outbreaks of food poisoning have caused significant mortality rates. Shiga toxins, are AB5 toxins that gain entry into human cells by recognizing and binding to the Pk trisaccharide component of the membrane glycosphingolipid receptor Gb3. A bifunctional ligand that incorporates Pk trisaccharide and a cyclic pyruvate acetal that binds to human serum amyloid P component (HuSAP), facilitates simultaneous binding of the B5 subunit of Shiga toxins with HuSAP as a supramolecular complex. The incorporation of the heterobifunctional ligand into a polymeric scaffold affords an increase in binding avidity over the low affinity of the trisaccharide ligand. When the multivalent bifunctional ligand was tested in a mouse model of Shigatoxemia, it was protective at low microgram doses. The synthesis of a disaccharide Pk analogue is described whereby α-GalNAc replaces the terminal α-Gal residue and is co-crystallized with Stx2. This co-crystal structure confirms previous inferences that two of the primary binding sites identified in the B5 pentamer of Stx1 are also functional in Stx2. This knowledge provides a rationale for the synthesis and evaluation of heterobifunctional antagonists for E. coli toxins that target Stx2.

  • Subjects / Keywords
  • Graduation date
    2014-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3ZG6GF08
  • 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)
    • Bundle, David R (Chemistry)
  • Examining committee members and their departments
    • Clive, Derrick L J (Chemistry)
    • Klassen, John (Chemistry)
    • Lowary, Todd L (Chemistry)
    • Szymanski, Christine M (Biology)
    • Field, Rob (Biological Chemistry)