Design and Synthesis of Galactosylated Bifurcated Ligands with Nanomolar Affinity for Lectin LecA from <i>Pseudomonas aeruginosa</i>

Angeli, Anthony; Li, Muchen; Dupin, Lucie; Vergoten, Gérard; Noël, Mathieu; Madaoui, Mimouna; Wang, Shuai; Meyer, Albert; Géhin, Thomas; Vidal, Sébastien; Vasseur, Jean‐Jacques; Chevolot, Yann; Morvan, François

doi:10.1002/cbic.201700154

Cited by 23 publications

(23 citation statements)

References 58 publications

(100 reference statements)

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“…After studying the impact of the cluster density, they have been able to identify nanomolar inhibitors for the lectin LecA from Pseudomonas aeruginosa . 25 All of these studies clearly demonstrated that the spatial arrangement of multivalent structures on surfaces favors stronger interactions with lectins than with monovalent ligands. However, these experiments allowed discrimination of ligands with significant differences in valency, thus leading to predictable data in the majority of cases.…”

Section: Introductionmentioning

confidence: 93%

Identification of Nanomolar Lectin Ligands by a Glycodendrimer Microarray

et al. 2018

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Carbohydrate–protein interactions play key roles in a wide variety of biological processes. These interactions are usually weak, with dissociation constants in the low millimolar to high micromolar range. Nature uses multivalency to reach high avidities via the glycoside cluster effect. Capitalizing on this effect, numerous synthetic multivalent glycoconjugates have been described and used as ligands for carbohydrate-binding proteins. However, valency is only one of the several parameters governing the binding mechanisms that are different for every biological receptor, making it almost impossible to predict. In this context, ligand optimization requires the screening of a large number of structures with different valencies, rigidities/flexibilities, and architectures. In this article, we describe a screening platform based on a glycodendrimer array and its use to determine the key parameters for high-affinity ligands of lectin. Several glycoclusters and glycodendrimers displaying varying numbers of α-N-acetylgalactosamine residues were covalently attached on glass slides, and their bindings were studied with the fluorophore-functionalized Helix pomatia agglutinin (HPA) used as a lectin model. This technique requires minimal quantities of glycoconjugate compared to those for other techniques and affords useful information on the binding strength. Building of the glycodendrimer array and quantification of the interactions with HPA are described.

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Section: Introductionmentioning

confidence: 93%

Identification of Nanomolar Lectin Ligands by a Glycodendrimer Microarray

et al. 2018

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“…In the chelate binding mode, multivalent ligands occupy at least two binding sites of the multivalent receptor (the lectin) simultaneously.A fter the first interaction, subsequent binding events are favoredo ver dissociation of the ligand-receptor complex, due to the high ligand concentration in close proximity to additional receptor binding sites and to the lower entropic cost of subsequent binding events. Chelate interactions have been shown to improve the affinity of clustered sugars compared with their monovalent references by severalo rders of magnitude on several multimeric lectin targets, [7][8][9] such as wheat germ agglutinin (WGA), [10] Shiga-like toxins from Escherichiac oli, [11][12][13] LecA and LecB lectinsf rom Pseudomonas aeruginosa, [14][15][16][17][18][19][20][21] dendritic-cell-specific ICAM-3 grabbing non-integrin( DC-SIGN), [22][23][24][25] and PHL from Gram-negative Photorhabdus asymbiotica. [26] In comparison, multivalent fucosides of FleA have been little studied,w ith the exception of au nique, recent report of ap otent hexavalent aryl-fucose mimetic.…”

Section: Introductionmentioning

confidence: 99%

Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes

Lehot

Brissonnet

Dussouy

et al. 2018

Chemistry A European J

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FleA (or AFL), a fucose lectin, was recently identified in the opportunistic mold Aspergillus fumigatus, which causes fatal lung infections in immunocompromised patients. We designed di‐, hexa‐ and octavalent fucosides with various spacer arm lengths to block the hexameric FleA through chelation. Microcalorimetry measurements showed that the ethylene glycol (EG) spacer arm length has a strong influence on the binding affinity of the divalent fucosides. The relationship between the EG length and chelate binding efficiency to FleA was explored according to polymer theory. Hexa‐ and octavalent compounds based on cyclodextrin and octameric silsesquioxane scaffolds were nanomolar FleA inhibitors, surpassing their monovalent fucose analogue by more than three orders of magnitude. Importantly, some of the fucosides were highly efficient in preventing fungal spore adhesion to bronchoepithelial cells, with half maximal inhibitory concentration values in the micromolar range. We propose that the synergistic antiadhesive effect observed can be ascribed to chelate binding to FleA and to the formation of conidium aggregates, as observed by optical microscopy. These fucosides are promising tools that can be used to better understand the role of FleA in conidia pathogenicity and host defenses against invasive aspergillosis.

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“…[16] Another approach to enhancei nhibitor interaction to LecA is through multivalent binding. Because LecA is at etrameric lectin andt he two closest binding sites are separated by about 26 , [17] various artificial scaffolds including dendrimers, [11,[18][19][20][21][22][23][24] clusters, [12][13][14][25][26][27][28][29][30][31][32] and linear rigid spacers [33][34][35][36] have been exploited to present galactoside ligands to theb inding sites to enhancei nhibition activity. [37] In other cases, the artificial scaffoldsa re furtherf unctionalized to generate extra interactions with LecA for stronger binding.…”

Section: Introductionmentioning

confidence: 99%

Development of Pseudomonas aeruginosa Lectin LecA Inhibitor by using Bivalent Galactosides Supported on Polyproline Peptide Scaffolds

Huang

Lin

Lai

et al. 2018

Chemistry An Asian Journal

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LecA is a galactose-binding tetrameric lectin from Pseudomonas aeruginosa involved in infection and biofilm formation. The emergent antibiotic resistance of P. aeruginosa has made LecA a promising pharmaceutical target to treat such infections. To develop LecA inhibitors, we exploit the unique helical structure of polyproline peptides to create a scaffold that controls the galactoside positions to fit their binding sites on LecA. With a modular scaffold design, both the galactoside ligands and the inter-ligand distance can be altered conveniently. We prepared scaffolds with spacings of 9, 18, 27, and 36 Å for ligand conjugation and found that glycopeptides with galactosides ligands three helical turns (27 Å) apart best fit LecA. In addition, we tested different galactose derivatives on the selected scaffold (27 Å) to improve the binding avidity to LecA. The results validate a new multivalent scaffold design and provide useful information for LecA inhibitor development.

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Design and Synthesis of Galactosylated Bifurcated Ligands with Nanomolar Affinity for Lectin LecA from Pseudomonas aeruginosa

Cited by 23 publications

References 58 publications

Identification of Nanomolar Lectin Ligands by a Glycodendrimer Microarray

Identification of Nanomolar Lectin Ligands by a Glycodendrimer Microarray

Multivalent Fucosides with Nanomolar Affinity for the Aspergillus fumigatus Lectin FleA Prevent Spore Adhesion to Pneumocytes

Development of Pseudomonas aeruginosa Lectin LecA Inhibitor by using Bivalent Galactosides Supported on Polyproline Peptide Scaffolds

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