Toxins 2011, 3(9), 1065-1088; doi:10.3390/toxins3091065
Article

Impact of the Nature and Size of the Polymeric Backbone on the Ability of Heterobifunctional Ligands to Mediate Shiga Toxin and Serum Amyloid P Component Ternary Complex Formation

1 Department of Chemistry, Alberta Ingenuity Centre for Carbohydrate Science, University of Alberta, Edmonton AB, Canada T6G 2G2 2 Department of Chemical Engineering, University of Alberta, Edmonton AB, Canada 3 Department of Microbiology, Immunology, and Infectious Diseases, Alberta Ingenuity Centre for Carbohydrate Science, University of Calgary, Calgary, AB, Canada T2N 4N1
* Authors to whom correspondence should be addressed.
Received: 14 July 2011; in revised form: 16 August 2011 / Accepted: 19 August 2011 / Published: 25 August 2011
(This article belongs to the Special Issue Shiga Toxin)
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Abstract: Inhibition of AB5-type bacterial toxins can be achieved by heterobifunctional ligands (BAITs) that mediate assembly of supramolecular complexes involving the toxin’s pentameric cell membrane-binding subunit and an endogenous protein, serum amyloid P component, of the innate immune system. Effective in vivo protection from Shiga toxin Type 1 (Stx1) is achieved by polymer-bound, heterobifunctional inhibitors-adaptors (PolyBAITs), which exhibit prolonged half-life in circulation and by mediating formation of face-to-face SAP-AB5 complexes, block receptor recognition sites and redirect toxins to the spleen and liver for degradation. Direct correlation between solid-phase activity and protective dose of PolyBAITs both in the cytotoxicity assay and in vivo indicate that the mechanism of protection from intoxication is inhibition of toxin binding to the host cell membrane. The polymeric scaffold influences the activity not only by clustering active binding fragments but also by sterically interfering with the supramolecular complex assembly. Thus, inhibitors based on N-(2-hydroxypropyl) methacrylamide (HPMA) show significantly lower activity than polyacrylamide-based analogs. The detrimental steric effect can partially be alleviated by extending the length of the spacer, which separates pendant ligand from the backbone, as well as extending the spacer, which spans the distance between binding moieties within each heterobifunctional ligand. Herein we report that polymer size and payload of the active ligand had moderate effects on the inhibitor’s activity.
Keywords: E. coli O157:H7; multivalent inhibitors; Pk-trisaccharide; Gb3

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MDPI and ACS Style

Kitov, P.I.; Paszkiewicz, E.; Sadowska, J.M.; Deng, Z.; Ahmed, M.; Narain, R.; Griener, T.P.; Mulvey, G.L.; Armstrong, G.D.; Bundle, D.R. Impact of the Nature and Size of the Polymeric Backbone on the Ability of Heterobifunctional Ligands to Mediate Shiga Toxin and Serum Amyloid P Component Ternary Complex Formation. Toxins 2011, 3, 1065-1088.

AMA Style

Kitov PI, Paszkiewicz E, Sadowska JM, Deng Z, Ahmed M, Narain R, Griener TP, Mulvey GL, Armstrong GD, Bundle DR. Impact of the Nature and Size of the Polymeric Backbone on the Ability of Heterobifunctional Ligands to Mediate Shiga Toxin and Serum Amyloid P Component Ternary Complex Formation. Toxins. 2011; 3(9):1065-1088.

Chicago/Turabian Style

Kitov, Pavel I.; Paszkiewicz, Eugenia; Sadowska, Joanna M.; Deng, Zhicheng; Ahmed, Marya; Narain, Ravin; Griener, Thomas P.; Mulvey, George L.; Armstrong, Glen D.; Bundle, David R. 2011. "Impact of the Nature and Size of the Polymeric Backbone on the Ability of Heterobifunctional Ligands to Mediate Shiga Toxin and Serum Amyloid P Component Ternary Complex Formation." Toxins 3, no. 9: 1065-1088.

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