Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene

Garcia-Hartjes, Jaime; Bernardi, Silvia; Weijers, C.A.G.M.; Wennekes, Tom; Gilbert, Michel; Sansone, Francesco; Casnati, Alessandro; Zuilhof, Han

doi:10.1039/c3ob40515j

Cited by 51 publications

(46 citation statements)

References 35 publications

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“…Later on, Marra et al [33] demonstrated that the copper-catalyzed azide–alkyne cycloaddition (CuAAC) [34–35] at room temperature could afford divalent and tetravalent glycocalixarenes in very high yields and regioselectivity. Following these studies, a wide series of other examples appeared in the literature [18,36–39] also exploiting the use of microwaves, ionic liquids and protected or even deprotected [17] saccharides. Usually, either the strategy of reacting an alkynylated-saccharide with a polyazide calixarene (dipolarophile-on-the-sugar) or an azido-sugar and a polyalkynocalixarene (dipolarophile-on-the-calix) work smoothly [33].…”

Section: Resultsmentioning

confidence: 99%

“…Glycocalixarenes [9–12], calixarenes [13–15] adorned with carbohydrates at the upper and/or at the lower rims, have been demonstrated to be efficient multivalent ligands for a series of pathological lectins. For instance, cholera toxin is bound rather efficiently by calix[4]arene [16] and calix[5]arene [17] derivatives, while examples of Pseudomonas aeruginosa LecB binding were reported with galactosylcalixarenes blocked in different conformations [18–19]. A few years ago we [20–21] reported about the synthesis and inhibitory properties of a small library of lactosylthioureidocalixarenes and found that the cone derivatives I and III (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

Bernardi¹,

Fezzardi²,

Rispoli³

et al. 2014

Beilstein J. Org. Chem.

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SummaryFour novel calix[4]arene-based glycoclusters were synthesized by conjugating the saccharide units to the macrocyclic scaffold using the CuAAC reaction and using long and hydrophilic ethylene glycol spacers. Initially, two galactosylcalix[4]arenes were prepared starting from saccharide units and calixarene cores which differ in the relative dispositions of the alkyne and azido groups. Once the most convenient synthetic pathway was selected, two further lactosylcalix[4]arenes were obtained, one in the cone, the other one in the 1,3-alternate structure. Preliminary studies of the interactions of these novel glycocalixarenes with galectin-3 were carried out by using a lectin-functionalized chip and surface plasmon resonance. These studies indicate a higher affinity of lactosyl- over galactosylcalixarenes. Furthermore, we confirmed that in case of this specific lectin binding the presentation of lactose units on a cone calixarene is highly preferred with respect to its isomeric form in the 1,3-alternate structure.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

Bernardi¹,

Fezzardi²,

Rispoli³

et al. 2014

Beilstein J. Org. Chem.

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“…Lately the search has turned towards multivalent inhibitors 36 , e.g . using pentavalent GM1-os on different scaffolds, creating a 1:1 interaction of toxin and inhibitor 37, 38 . An interesting approach is to “let CT fight itself” using CTB modified with GM1-os residues as penta-GM1-os-CTB neoglycoprotein inhibitors 39 .…”

Section: Introductionmentioning

confidence: 99%

Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics

Heggelund

Mackenzie

Martinsen

et al. 2017

Sci Rep

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Cholera is a life-threatening disease in many countries, and new drugs are clearly needed. C-glycosidic antagonists may serve such a purpose. Here we report atomic-resolution crystal structures of three such compounds in complexes with the cholera toxin. The structures give unprecedented atomic details of the molecular interactions and show how the inhibitors efficiently block the GM1 binding site. These molecules are well suited for development into low-cost prophylactic drugs, due to their relatively easy synthesis and their resistance to glycolytic enzymes. One of the compounds links two toxin B-pentamers in the crystal structure, which may yield improved inhibition through the formation of toxin aggregates. These structures can spark the improved design of GM1 mimics, either alone or as multivalent inhibitors connecting multiple GM1-binding sites. Future developments may further include compounds that link the primary and secondary binding sites. Serving as decoys, receptor mimics may lessen symptoms while avoiding the use of antibiotics.

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“…[5b, 6] Other recent studies have used GM1os ligands on both corannulene [7] and calixarene cores. [8] These pentavalent structures gave IC 50 values down to 5 nm and 450 pm, respectively. A pentameric carbohydrate core has also been used in the highly effective Starfish ligands for shiga-like toxin.…”

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confidence: 99%

“…[7,8] The ability of CTB to bind to a GM1-coated microtiter plate was assessed across a wide range of inhibitor concentrations. Pentavalent ligand W88E(GM1) exhibited an exceptionally low IC 50 value of 104 pm ( Figure 2 and Table 1), making it the most potent pentavalent ligand reported thus far.…”

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confidence: 99%

A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit

et al. 2014

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Protein toxins produced by bacteria are the cause of many life-threatening diarrheal diseases. Many of these toxins, including cholera toxin (CT), enter the cell by first binding to glycolipids in the cell membrane. Inhibiting these multivalent protein/carbohydrate interactions would prevent the toxin from entering cells and causing diarrhea. Here we demonstrate that the site-specific modification of a protein scaffold, which is perfectly matched in both size and valency to the target toxin, provides a convenient route to an effective multivalent inhibitor. The resulting pentavalent neoglycoprotein displays an inhibition potency (IC 50 ) of 104 pm for the CT B-subunit (CTB), which is the most potent pentavalent inhibitor for this target reported thus far. Complexation of the inhibitor and CTB resulted in a protein heterodimer. This inhibition strategy can potentially be applied to many multivalent receptors and also opens up new possibilities for protein assembly strategies.

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Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene

Cited by 51 publications

References 35 publications

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: new multivalent galectin-3 ligands

Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics

A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit

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