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      A hybrid polymer to target blood group dependence of cholera toxin

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          Abstract

          New hybrid glycopolymers were synthesized that contain two epitopes blocking GM1- and fucose-based intoxication modes of the cholera toxin.

          Abstract

          Cholera is a potentially fatal bacterial infection caused by the cholera toxin (CT), an AB 5 toxin secreted by Vibrio cholera. GM1 has long been known as the receptor of the cholera toxin in the intestine. However, increasing evidence is pointing towards the role of fucosylated conjugates as additional attachment options of the toxin. In the present paper we have synthesized a polymeric hybrid which can inhibit both modes of attachment.

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          Bridging lectin binding sites by multivalent carbohydrates.

          Carbohydrate-protein interactions are involved in a multitude of biological recognition processes. Since individual protein-carbohydrate interactions are usually weak, multivalency is often required to achieve biologically relevant binding affinities and selectivities. Among the possible mechanisms responsible for binding enhancement by multivalency, the simultaneous attachment of a multivalent ligand to several binding sites of a multivalent receptor (i.e. chelation) has been proven to have a strong impact. This article summarizes recent examples of chelating lectin ligands of different size. Covered lectins include the Shiga-like toxin, where the shortest distance between binding sites is ca. 9 Å, wheat germ agglutinin (WGA) (shortest distance between binding sites 13-14 Å), LecA from Pseudomonas aeruginosa (shortest distance 26 Å), cholera toxin and heat-labile enterotoxin (shortest distance 31 Å), anti-HIV antibody 2G12 (shortest distance 31 Å), concanavalin A (ConA) (shortest distance 72 Å), RCA120 (shortest distance 100 Å), and Erythrina cristagalli (ECL) (shortest distance 100 Å). While chelating binding of the discussed ligands is likely, experimental proof, for example by X-ray crystallography, is limited to only a few cases.
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            Cholera Toxin B: One Subunit with Many Pharmaceutical Applications

            Cholera, a waterborne acute diarrheal disease caused by Vibrio cholerae, remains prevalent in underdeveloped countries and is a serious health threat to those living in unsanitary conditions. The major virulence factor is cholera toxin (CT), which consists of two subunits: the A subunit (CTA) and the B subunit (CTB). CTB is a 55 kD homopentameric, non-toxic protein binding to the GM1 ganglioside on mammalian cells with high affinity. Currently, recombinantly produced CTB is used as a component of an internationally licensed oral cholera vaccine, as the protein induces potent humoral immunity that can neutralize CT in the gut. Additionally, recent studies have revealed that CTB administration leads to the induction of anti-inflammatory mechanisms in vivo. This review will cover the potential of CTB as an immunomodulatory and anti-inflammatory agent. We will also summarize various recombinant expression systems available for recombinant CTB bioproduction.
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              Fucosylation and protein glycosylation create functional receptors for cholera toxin

              Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors using its B subunit (CTB). The ganglioside (glycolipid) GM1 is thought to be the sole CT receptor; however, the mechanism by which CTB binding to GM1 mediates internalization of CT remains enigmatic. Here we report that CTB binds cell surface glycoproteins. Relative contributions of gangliosides and glycoproteins to CTB binding depend on cell type, and CTB binds primarily to glycoproteins in colonic epithelial cell lines. Using a metabolically incorporated photocrosslinking sugar, we identified one CTB-binding glycoprotein and demonstrated that the glycan portion of the molecule, not the protein, provides the CTB interaction motif. We further show that fucosylated structures promote CTB entry into a colonic epithelial cell line and subsequent host cell intoxication. CTB-binding fucosylated glycoproteins are present in normal human intestinal epithelia and could play a role in cholera. DOI: http://dx.doi.org/10.7554/eLife.09545.001
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                Author and article information

                Journal
                OBCRAK
                Organic & Biomolecular Chemistry
                Org. Biomol. Chem.
                Royal Society of Chemistry (RSC)
                1477-0520
                1477-0539
                2020
                2020
                : 18
                : 1
                : 52-55
                Affiliations
                [1 ]Department of Chemical Biology & Drug Discovery
                [2 ]Utrecht Institute for Pharmaceutical Sciences
                [3 ]Utrecht University
                [4 ]3508 TB Utrecht
                [5 ]The Netherlands
                Article
                10.1039/C9OB02369K
                2c8f8036-3f3b-45ea-aafa-5f1c65112817
                © 2020

                http://creativecommons.org/licenses/by/3.0/

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