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Permanent link (DOI): https://doi.org/10.7939/R3ZG6GF08

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

Descriptions

Other title
Subject/Keyword
Chemistry
Carbohydrates
Shiga toxin
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Jacobson, Jared M
Supervisor and department
Bundle, David R (Chemistry)
Examining committee member and department
Szymanski, Christine M (Biology)
Klassen, John (Chemistry)
Lowary, Todd L (Chemistry)
Field, Rob (Biological Chemistry)
Clive, Derrick L J (Chemistry)
Department
Department of Chemistry
Specialization

Date accepted
2013-12-20T14:56:23Z
Graduation date
2014-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R3ZG6GF08
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Kitov, P. I.; Mulvey, G. L.; Griener, T. P.; Lipinski, T.; Solomon, D.; Paszkiewicz, E.; Jacobson, J. M.; Sadowska, J. M.; Suzuki, M.; Yamamura, K. I.; Armstrong, G. D.; Bundle, D. R. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 16837-16842.Jacobson, J. M.; Kitov, P. I.; Bundle, D. R. Carbohydr. Res. 2013, 378, 4-14.Jacobson, J. M.; Yin, J.; Kitov, P. I.; Mulvey, G.; Griener, T. P.; James, M. N. G.; Armstrong, G.; Bundle, D. R. J. Biol. Chem. 2013, In press.

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File title: Jacobson Thesis Final
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