Polyvalent Transition‐State Analogues of Sialyl Substrates Strongly Inhibit Bacterial Sialidases**

assailly, coralie; Bridot, Clarisse; Saumonneau, Amélie; lottin, paul; Roubinet, Benoît; Krammer, Eva-Maria; François, francesca; Vena, Federica; Landemarre, Ludovic; Álvarez-Dorta, Dimitri; Deniaud, David; Grandjean, Cyrille; Tellier, Charles; Pascual, Sagrario; Montembault, Véronique; Fontaine, Laurent; Daligault, Franck; Bouckaert, Julie; Gouin, Sébastien G.

doi:10.1002/chem.202004672

Cited by 11 publications

(18 citation statements)

References 51 publications

(106 reference statements)

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“…over the 33 reactive groups present in 3) were conjugated to 3 by CuAAC, with tris(benzyltriazolylmethyl)amine (TBTA), L-sodium ascorbate and CuSO 4 in PBS similarly to previous reports. [26,27,28] After 24 h at room temperature, the resulting homovalent neoGPs 4 a-c were purified on Sephadex G25. The purity was confirmed by SDS-PAGE and MALDI-TOF experiments enabled to estimate that between 12 to 19 tetravalent glycodendrons were coupled to BSA, which corresponds to 49-75 glycans per BSA and molecular weights from 92 to 105 kDa for homovalent neoGPs 4 a-c (Table 1, FigureS11 and S14).…”

Section: Synthesis Of Neogpsmentioning

confidence: 99%

“…The binding ability of the homovalent neoGPs 4 a-c was studied with LecA and LecB using the GLYcoPROFILE® technology (GLYcoDiag, France). [26,27,28,31] NeoGPs 4 a-c were first labelled with biotin using the protocol described previously then were incubated in microtitration plates coated with lectins. Streptavidin labelled with 5-(4,6-dichlorotriazinyl)-aminofluorescein (DTAF) was finally incubated in each well and the interaction was directly detected by reading the fluorescence intensity (FI) provided by the neoGP bound to the lectin.…”

Section: Direct Binding Assaysmentioning

confidence: 99%

“…To confirm these observations, we next performed inhibition assays with LecA and LecB using biotinylated neoGPs as tracers (respectively neoGP 4 a for LecA and neoGP 4 c for LecB). [31,26,27,28] The neoGPs 4 a-c and 5, the two commercial neoglycoproteins NeoGa and NeoF functionalized with monovalent αGal or αFuc (grafting ratio of 13 and 14 units, respectively), and the corresponding monosaccharides have been tested as inhibitors (Table 2). In this assay, lectin is immobilized in microplate wells and simultaneously incubated with a solution containing the biotinylated tracer and various concentration of the inhibitors.…”

Section: Inhibition Assaysmentioning

confidence: 99%

“…The assays were performed according GlycoDiag's protocol already described. [26,27,28,31] For direct binding mode, each neoglycoproteins were preliminary labeled with biotin according to standard protocol already described. [28] Briefly, the different compounds (range of concentrations) prepared in PBS supplemented with 1 mM CaCl 2 and 0.5 mM MgCl 2 were deposited in each well of lectin (50 μL each) in triplicate and incubated for two hours at room temperature.…”

Section: Direct Binding Assaysmentioning

confidence: 99%

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Homo‐ and Heterovalent Neoglycoproteins as Ligands for Bacterial Lectins

Goyard

Roubinet²,

Vena³

et al. 2021

ChemPlusChem

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Click chemistry gives access to unlimited set of multivalent glycoconjugates to explore carbohydrate-protein interactions and discover high affinity ligands. In this study, we have created supramolecular systems based on a carrier protein that was grafted by Cu(I)-catalyzed azide-alkyne cycloaddition with tetravalent glycodendrons presenting αGal, βGal and/or αFuc. Binding studies of the homo-(4 a-c) and heterovalent ( 5) neoglycoproteins (neoGPs) with the LecA and LecB lectins from P. aeruginosa has first confirmed the interest of the multivalent presentation of glycodendrons by the carrier protein (IC 50 up to 2.8 nM). Moreover, these studies have shown that the heterovalent display of glycans (5) allows the interaction with both lectins (IC 50 of 10 nM) despite the presence of unspecific moieties, and even with similar efficiency for LecB. These results demonstrate the potential of multivalent and multispecific neoGPs as a promising strategy to fight against resistant pathogens.

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Section: Synthesis Of Neogpsmentioning

confidence: 99%

Section: Direct Binding Assaysmentioning

confidence: 99%

Section: Inhibition Assaysmentioning

confidence: 99%

Section: Direct Binding Assaysmentioning

confidence: 99%

See 2 more Smart Citations

Homo‐ and Heterovalent Neoglycoproteins as Ligands for Bacterial Lectins

Goyard

Roubinet²,

Vena³

et al. 2021

ChemPlusChem

Self Cite

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“…Indeed, it was shown that the binding modes of Jack Bean α-mannosidases with iminosugar-based multivalent inhibitors not only depend on the nature and number of bioactive inhitopes, but more importantly on the shape and size of the multivalent scaffold as well as ligand density [ 15 , 16 , 17 , 18 , 19 , 20 ]. Multimerization of inhitopes proved to be an attractive strategy, enabling valency-corrected inhibition enhancements of up to three [ 26 ] to four [ 27 ] orders of magnitude, inhibition selectivity refining or enzyme activation [ 28 , 29 ]. Multivalent drugs on nanoparticles also proved efficient for escaping efflux pumps [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents

et al. 2022

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Bambusurils, BU[4] and BU[6], were used for the first time as multivalent scaffolds to link glycosidases inhibitors derived from 1-deoxynojirimycin (DNJ). Two linear DNJ ligands having six or nine carbon alkyl azido linkers or a trivalent DNJ dendron were grafted onto octapropargylated BU[4] and dodecapropargylated BU[6] using copper-catalyzed cycloaddition (CuAAC) to yield corresponding neoglycobambus[4] and neoglycobambus[6]urils bearing 8 to 24 iminosugars. The inhibition potencies of neoglycoBU[4], neoglycoBU[6] and neoglycoBU[6] caging anions were evaluated against Jack Bean α-mannosidase and compared to monovalent DNJ derivatives. Strong affinity enhancements per inhibitory head were obtained for the clusters holding trivalent dendrons with inhibitory constants in the nanomolar range (Ki = 24 nM for BU[4] with 24 DNJ units). Interestingly, the anion (bromide or iodide) encapsulated inside the cavity of BU[6] does not modify the inhibition potency of neoglycoBU[6], opening the way to water-soluble glycosidase-directed anion caging agents that may find applications in important fields such as bio(in)organic chemistry or oncology.

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Deconstructing Best‐in‐Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase Inhibition

Liang,

Schettini,

Kern

et al. 2024

Chemistry A European J

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Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non‐polymeric glycosidase inhibitor have been obtained with cyclopeptoid‐based inhibitors of Jack bean α‐mannosidase (JBα‐man). Here, we report a structure‐activity relationship (SAR) study based on the top‐down deconstruction of best‐in‐class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate‐binding, resulting from the formation of a cross‐linked complex between a multivalent inhibitor and two dimeric JBα‐man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors.

show abstract

Polyvalent Transition‐State Analogues of Sialyl Substrates Strongly Inhibit Bacterial Sialidases**

Abstract: Supporting information for this article is available.

Cited by 11 publications

References 51 publications

Homo‐ and Heterovalent Neoglycoproteins as Ligands for Bacterial Lectins

Homo‐ and Heterovalent Neoglycoproteins as Ligands for Bacterial Lectins

Bambus[4,6]urils as Dual Scaffolds for Multivalent Iminosugar Presentation and Ion Transport: Access to Unprecedented Glycosidase-Directed Anion Caging Agents

Deconstructing Best‐in‐Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase Inhibition

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