Synthesis of Multivalent Carbohydrate‐Centered Glycoclusters as Nanomolar Ligands of the Bacterial Lectin LecA from Pseudomonas aeruginosa

Abstract

A family of fifteen glycoclusters based on a cyclic oligo-(1→6)-β-D-glucosamine core has been designed as potential inhibitors of the bacterial lectin LecA with various valencies (from 2 to 4) and linkers. Evaluation of their binding properties towards LecA has been performed by a combination of hemagglutination inhibition assays (HIA), enzyme-linked lectin assays (ELLA), and isothermal titration microcalorimetry (ITC). Divalent ligands displayed dissociation constants in the sub-micromolar range and tetravalent ligands displayed low nanomolar affinities for this lectin. The influence of the linker could also be demonstrated; aromatic moieties are the best scaffolds for binding to the lectin. The affinities observed in vitro were then correlated with molecular models to rationalize the possible binding modes of these glycoclusters with the bacterial lectin.

A LecA Ligand Identified from a Galactoside‐Conjugate Array Inhibits Host Cell Invasion by Pseudomonas aeruginosa

“…[2,3] It was demonstrated in a P. aeruginosa model of infection that the lectin is involved in lung injury and mortality [4][5][6][7] and recent data suggested that LecA promotes bacterial invasion into host cells. [9,15] These studies clearly highlighted the potential benefit of oligovalent interactions since dissociation constants lower than 90 nm and 20 nm were obtained for tetravalent [11,16] and divalent [13] compounds, respectively. 30 .…”

“…[1] In the case of P. aeruginosa, the structural basis for the preference of the LecA lectin towards galactose and globotriaosylceramide (Gb3) was elucidated. This structural knowledge has stimulated intense work to design templates presenting galactose residues with a spacing that matches the dimeric geometry of LecA neighboring binding sites [8][9][10][11][12][13][14][15][16] with the potential of acting as anti-pathogenic agents [17,18] or disrupting biofilm formation. [7] The lectin is a tetramer and structural data demonstrated an overall rectangular shape with pairing of neighboring binding sites separated by ca.…”

Importance of topology for glycocluster binding to Pseudomonas aeruginosa and Burkholderia ambifaria bacterial lectins

“…13,[32][33][34][35][36][37][38] Nevertheless, the topology brings an additional benefit allowing high binding with only trivalent clusters.…”

Glycoconjugates of porphyrins with carbohydrates: methods of synthesis and biological activity

“…It is noteworthy that tetragalactoside based on the cyclo-oligoglucosamine scaffold synthesized by our research group is currently the most highaffinity ligand for the lectin PA-IL (K D = 8610 78 mol litre 71 ). 146 Vidal's and Imberty's studies dealing with the synthesis of lectin blocking agents based on the porphyrin scaffold were continued by Cecioni et al, 147 who described the preparation of tetralactosylporphyrin 229. The interaction of this compound with lectins ECA and galectin-1 (also specific to galactose) was studied by HIA, SPR and enzymelinked lectin assay (ELLA).…”