Fucosylated inhibitors of recently identified bangle lectin from Photorhabdus asymbiotica

Abstract

A recently described bangle lectin (PHL) from the bacterium Photorhabdus asymbiotica was identified as a mainly fucose-binding protein that could play an important role in the host-pathogen interaction and in the modulation of host immune response. Structural studies showed that PHL is a homo-dimer that contains up to seven l-fucose-specific binding sites per monomer. For these reasons, potential ligands of the PHL lectin: α-l-fucopyranosyl-containing mono-, di-, tetra-, hexa- and dodecavalent ligands were tested. Two types of polyvalent structures were investigated – calix[4]arenes and dendrimers. The shared feature of all these structures was a C-glycosidic bond instead of the more common but physiologically unstable O-glycosidic bond. The inhibition potential of the tested structures was assessed using different techniques – hemagglutination, surface plasmon resonance, isothermal titration calorimetry, and cell cross-linking. All the ligands proved to be better than free l-fucose. The most active hexavalent dendrimer exhibited affinity three orders of magnitude higher than that of standard l-fucose. To determine the binding mode of some ligands, crystal complex PHL/fucosides 2 – 4 were prepared and studied using X-ray crystallography. The electron density in complexes proved the presence of the compounds in 6 out of 7 fucose-binding sites.

Glycocalix[4]arenes and their affinity to a library of galectins: the linker matters

“…19 Glycocalixarenes can be obtained through amidation, 20, 21 1,3dipolar cycloaddition ("click reaction"), 22, 23 1,3-dipolar nitronealkene cycloaddition, 24 or through conjugation of amine and isothiocyanate functions. 25 Glycocalixarenes have previously been exploited as ligands of lectins of pathogenic bacteria, e.g., BC 2 L-C lectin of Burkholderia cenocepacia, 26 RSL lectin from Ralstonia solanacearum, 26 PHL lectin of Photorhabdus asymbiotica, 27 cholera toxin, 21 PA-IL and PA-IIL lectins of Pseudomonas aeruginosa, 26,28,29 or fungi, such as AFL lectin of Aspergillus fumigatus, AOL of Aspergillus oryzae, or AAL of Aleuria aurantia. 26 In 2008, the first publication on glycocalixarene ligands of human galectins was published by André, Sansone, and coworkers.…”

“…25 Glycocalixarenes have previously been exploited as ligands of lectins of pathogenic bacteria, e.g. , BC 2 L-C lectin of Burkholderia cenocepacia , 26 RSL lectin from Ralstonia solanacearum , 26 PHL lectin of Photorhabdus asymbiotica , 27 cholera toxin, 21 PA-IL and PA-IIL lectins of Pseudomonas aeruginosa , 26,28,29 or fungi, such as AFL lectin of Aspergillus fumigatus , AOL of Aspergillus oryzae , or AAL of Aleuria aurantia . 26…”

Rim-differentiation vs. mixture of constitutional isomers: A binding study between pillar[5]arene-based glycoclusters and lectins from pathogenic bacteria

“…Among strategies that have been developed to competitively interfere with the recognition processes between host cells and pathogens, multivalent glycoconjugates have the potential to prevent colonization or even reverse the formation of biofilms for fighting bacterial infection. Therefore, a large number of glycoclusters have been constructed based on various scaffolds including proteins [18,19], polymers [20,21], dendrimers [22], calixarenes [23][24][25][26][27][28][29][30][31], resorcinarenes [32], cyclodextrins [33], porphyrins [34][35][36][37], fullerenes [38][39][40][41][42][43][44][45][46][47], and pillararenes [48][49][50][51], to prevent or treat diseases caused by bacteria. Pillar[n]arenes, as a novel family of macrocyclic host molecules [52][53][54], have been well-received by the supra(bio)molecular chemistry community since their first report in 2008 by Ogoshi [55].…”