Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands

Kitov, Pavel I.; Sadowska, Joanna; Mulvey, George L.; Armstrong, Glen D.; Li, Hong; Pannu, Navraj S.; Read, Randy J.; Bundle, David R.

doi:10.1038/35001095

Cited by 833 publications

(675 citation statements)

References 31 publications

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“…[176] Excellent examples of this chelation binding mode are presented in some recent studies directed at devising multivalent inhibitors of pentavalent toxins. [177][178][179] Similarly, certain receptors possess binding subsites in addition to their primary site of interaction. Unlike monovalent ligands, which can only access subsites adjacent to their primary binding pocket, multivalent ligands may gain binding energy from contacting these secondary sites.…”

Section: Mechanisms Of Multivalent Ligand Bindingmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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Cell surface receptors acquire information from the extracellular environment and coordinate intracellular responses. Evidence from biochemical and structural studies indicates that many receptors do not operate as individual entities, but rather as part of higher-order complexes (e.g. dimers and oligomers). Coupling the functions of multiple receptors may endow signaling pathways with the sensitivity and malleability required to govern cellular responses. Moreover, multireceptor signaling complexes may provide a means of spatially segregating otherwise degenerate signaling cascades. Despite the proposed importance of receptor-receptor processes in cellular signaling, questions concerning the mechanisms, extent, and consequences of receptor co-localization and interreceptor communication remain unanswered.Chemical synthesis can provide a variety of compounds with which to address the role of receptor assembly in signal transduction. The focus of this review is one such approach -the use of synthetic multivalent ligands to characterize receptor function. Multivalent ligands can be generated that possess a variety of sizes, shapes, valencies, orientations, and densities of binding elements. Their unique architectures imbue multivalent ligands with the ability to access binding modes not available to monovalent compounds. Multivalent ligands, therefore, are capable of illuminating aspects of inter-receptor processes that are not readily probed using conventional approaches. We suggest that, as focus shifts from investigations of the function of individual proteins and toward the analysis of multi-receptor signaling complexes, multivalent ligands will become even more valuable tools with which to ask sophisticated mechanistic questions. Further, multivalent ligands may provide new opportunities for manipulating receptor systems for the deconvolution of pathways, diagnosis, and, ultimately, the treatment of disease.

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Section: Mechanisms Of Multivalent Ligand Bindingmentioning

confidence: 99%

Synthetic Multivalent Ligands as Probes of Signal Transduction

2006

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“…Highly selective and potent binding of Stx to Gb 3 is mainly attributed to the multiple interaction of the B subunit pentamer with the trisaccharide moiety of Gb 3 . On the basis of these facts, several Stx neutralizers, in which the trisaccharide moiety of Gb 3 is combined with various core structures in multiple ways, have been reported (7)(8)(9)(10). However, no Stx neutralizer has been developed that is capable of detoxifying the toxin present in the circulation.…”

Section: S Higa Toxin (Stx)-producing Escherichia Coli (Stec) Includ-mentioning

confidence: 99%

A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

Nishikawa

Matsuoka

Kita

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

185

124

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Infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7, which causes diarrhea and hemorrhagic colitis in humans, often results in fatal systemic complications, such as neurological damage and hemolytic-uremic syndrome. Because Stx circulating in the blood is a major causative factor of these complications, the development of a Stx neutralizer that functions in the circulation holds promise as a viable therapy. Here we developed a series of carbosilane dendrimers, in which trisaccharides of globotriaosyl ceramide, a receptor for Stx, were variously oriented at their termini (referred to as SUPER TWIG), and identified a SUPER TWIG with six trisaccharides as a Stx neutralizer functioning in the circulation. This SUPER TWIG specifically bound to Stx with high affinity (Kd ‫؍‬ 1.1 ؋ 10 ؊6 M) and inhibited the incorporation of the toxin into target cells. Intravenous administration of the SUPER TWIG along with Stx to mice substantially reduced the fatal brain damage and completely suppressed the lethal effect of Stx. Moreover, the SUPER TWIG protected mice from challenge with a fatal dose of E. coli O157:H7, even when administered after the establishment of the infection. The SUPER TWIG neutralized Stx in vivo by a mechanism in which the accumulation and immediate degradation of Stx by phagocytic macrophages present in the reticuloendothelial system were induced. Taken together, our findings indicate that this SUPER TWIG is therapeutic agent against infections by Stx-producing E. coli.

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“…When the structure of Stx was solved, the carboxyl-terminal tail of the A-subunit was found to be surrounded by its five B-subunits like heat-labile enterotoxin, whereas the remainder of the A-subunit lay on one side of the B-pentamer (5). The determinations of the structures of the Stx1 B-subunits and of their mutated forms, alone and in complex with sugars, have led to a better understanding of the binding properties of the B-pentamer (6 -8) and have served as templates in the design of inhibitors to cell binding (9,10).…”

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confidence: 99%

Structure of Shiga Toxin Type 2 (Stx2) from Escherichia coli O157:H7

Fraser

Fujinaga

Cherney

et al. 2004

Journal of Biological Chemistry

260

278

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Several serotypes of Escherichia coli produce protein toxins closely related to Shiga toxin (Stx) from Shigella dysenteriae serotype 1. These Stx-producing E. coli cause outbreaks of hemorrhagic colitis and hemolytic uremic syndrome in humans, with the latter being more likely if the E. coli produce Stx2 than if they only produce Stx1. To investigate the differences among the Stxs, which are all AB 5 toxins, the crystal structure of Stx2 from E. coli O157:H7 was determined at 1.8-Å resolution and compared with the known structure of Stx. Our major finding was that, in contrast to Stx, the active site of the A-subunit of Stx2 is accessible in the holotoxin, and a molecule of formic acid and a water molecule mimic the binding of the adenine base of the substrate. Further, the A-subunit adopts a different orientation with respect to the B-subunits in Stx2 than in Stx, due to interactions between the carboxyl termini of the B-subunits and neighboring regions of the A-subunit. Of the three types of receptor-binding sites in the B-pentamer, one has a different conformation in Stx2 than in Stx, and the carboxyl terminus of the A-subunit binds at another. Any of these structural differences might result in different mechanisms of action of the two toxins and the development of hemolytic uremic syndrome upon exposure to Stx2.

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Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands

Cited by 833 publications

References 31 publications

Synthetic Multivalent Ligands as Probes of Signal Transduction

Synthetic Multivalent Ligands as Probes of Signal Transduction

A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

Structure of Shiga Toxin Type 2 (Stx2) from Escherichia coli O157:H7

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