Multivalent Glycomimetics with Affinity and Selectivity toward Fucose-Binding Receptors from Emerging Pathogens

Abstract

Bacterial and fungal pathogens involved in lung infection in cystic fibrosis patients utilize a particular family of glycan-binding proteins, characterized by the presentation of six fucose-binding sites on a ring-shaped scaffold. These lectins are attractive targets for anti-infectious compounds that could interfere in the recognition of host tissues by pathogens. The design of a cyclopeptide-based hexavalent structure allowed for the presentation of six fucose residues. The synthetic hexavalent compound displays liable geometry resulting in high-avidity binding by lectins from Aspergillus fumigatus and Burkholderia ambifaria. Replacing the fucose residue with a conformationally constrained fucomimetic does not alter the affinity and provides fine specificity with no binding to other fucose-specific lectins.

Molecular Recognition of a Thomsen–Friedenreich Antigen Mimetic Targeting Human Galectin‐3

“…Various efforts have been put forth to design different rigid ligands, in an attemptt om inimize the loss of conformational entropy upon complexc onformation;h owever,t hese approaches have usually provided minor advantages, far from an optimal solution,w hich is usually providedb yu sing multivalentp resentations of the ligand. [36,37] Nevertheless, from a mere phenomenological perspective,a nd although not completely understood, the present example illustrates the possibility of improving the entropy term by designing an amphiphilic artificial ligand that interacts at the same binding site as the natural counterpart. Although in this particular case the entropyg ain is compensated by as ignificant enthalpyl oss, it shows that av ery significant entropyg ain can be achieved by as imple modificationo ft he chemical nature of the ligand, keeping its basic binding features but generating an amphiphilic surface.…”

“…The systematic modulation of enthalpy and entropy to achieve improved binding is far from trivial. Various efforts have been put forth to design different rigid ligands, in an attempt to minimize the loss of conformational entropy upon complex conformation; however, these approaches have usually provided minor advantages, far from an optimal solution, which is usually provided by using multivalent presentations of the ligand . Nevertheless, from a mere phenomenological perspective, and although not completely understood, the present example illustrates the possibility of improving the entropy term by designing an amphiphilic artificial ligand that interacts at the same binding site as the natural counterpart.…”

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

“…Results from ITC experiments with fucosides 2 – 10 clearly showed a significant multivalent effect and a strong binding affinity for FleA adhesion. Multivalent fucose mimetics with strong affinity for FleA have recently been described, but their conidium antiadhesive potential was not reported. To evaluate this potential, we set up an inhibition assay on cells (Figure ).…”

“…Chelate interactions have been shown to improve the affinity of clustered sugars compared with their monovalent references by several orders of magnitude on several multimeric lectin targets, such as wheat germ agglutinin (WGA), Shiga‐like toxins from Escherichia coli , LecA and LecB lectins from Pseudomonas aeruginosa , dendritic‐cell‐specific ICAM‐3 grabbing non‐integrin (DC‐SIGN), and PHL from Gram‐negative Photorhabdus asymbiotica . In comparison, multivalent fucosides of FleA have been little studied, with the exception of a unique, recent report of a potent hexavalent aryl‐fucose mimetic …”

“…[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. [27] Here, we determined the critical parameters required for a multivalent glycoconjugate to tightly interact with the lectin FleA. Mono-, di-, hexa-, and octavalent fucosides with different sized oligo ethylene glycol (EG n )s pacers were designed to assess both the effect of ligand valency ands pacer arm length on the avidity effect.T he thermodynamic parameters of the binding interactions of the fucosides to FleA were measured using isothermal titration microcalorimetry (ITC).…”