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Permanent link (DOI): https://doi.org/10.7939/R37S7HS5J
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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. Open Access
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Kitov, P. I.
Sadowska, J .M.
Mulvey, G. L.
Armstrong, G. D.
Bundle, D. R.
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E. coli O157:H7
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- Journal Article (Published)
Inhibition of AB(5)-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-AB(5) 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.
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Kitov, P. I., Paszkiewicz, E., Sadowska, J .M., Deng, Z., Ahmed, M., Narain, R., Griener, T., 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, 3, 1065-1088, 2011.
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