Multivalent glycoconjugates as anti-pathogenic agents

Abstract

Multivalency plays a major role in biological processes and particularly in the relationship between pathogenic microorganisms and their host that involves protein-glycan recognition. These interactions occur during the first steps of infection, for specific recognition between host and bacteria, but also at different stages of the immune response. The search for high-affinity ligands for studying such interactions involves the combination of carbohydrate head groups with different scaffolds and linkers generating multivalent glycocompounds with controlled spatial and topology parameters. By interfering with pathogen adhesion, such glycocompounds including glycopolymers, glycoclusters, glycodendrimers and glyconanoparticles have the potential to improve or replace antibiotic treatments that are now subverted by resistance. Multivalent glycoconjugates have also been used for stimulating the innate and adaptive immune systems, for example with carbohydrate-based vaccines. Bacteria present on their surfaces natural multivalent glycoconjugates such as lipopolysaccharides and S-layers that can also be exploited or targeted in anti-infectious strategies.

Fig. 1

(a) Glycodendrofullerene 1 with 36 mannoses; (b) glycodendrimer 2 with 18 mannoses prepared using a CuAAC click reaction.

Fig. 2

Gold nanoparticles 3a–3d bearing high-mannose type glycans (manno–GNPs) present on HIV envelope glycoprotein gp120 as anti-HIV synthetic glycoconjugates.

Fig. 3

Bivalent glycoclusters 4 (acyclic) and 5 (macrocyclic), identified as sensors for different galectin subtypes.

Fig. 4

Structures of GM1os- (7a, 8a and 9a) and galactose (7b, 8b and 9b)-based inhibitors of cholera toxin binding.

Fig. 5

Structurally simplified GM1os mimic 10 grafted onto a functionalized calix[4]arene scaffold to give divalent ligand 11.

Fig. 6

Examples of various multivalent glycoconjugates inhibiting type 1 fimbriae-mediated bacterial adhesion. (a) Octopus glycosides 12; (b) glycodendrimer 13; (c) bifunctional ligand 14 to test multiple binding sites on FimH; (d) glyconanodiamonds to remove pathogenic bacteria from polluted water sources, a sandwich assay is displayed, utilizing two different bacterial strains.

Fig. 7

Dodecavalent mannofullerenes 15-20 as FimH inhibitors.

Fig. 8

Oligovalent galabiose derivatives.

Fig. 9

Multivalent glycoconjugates 22-33 as LecA high affinity ligands.

Fig. 10

Structure of glycopeptide dendrimer inhibitors of P. aeruginosa biofilms.

Fig. 11

Multivalent glycoconjugates 35-41 as LecB high affinity ligands.

Fig. 12

Divalent mannosylated compounds as ligands of BC2L.

Fig. 13

Use of galabiose-functionalized magnetic beads for identifying and isolating S. suis bacteria.

Fig. 14

Structure of the LPS from Rhizobium radiobacter Rv3. The area in the box displays strong structural similarity with the epitope recognized from the mAb 2G12. LA stands for lipid A.

Fig. 15

Multivalent glycosylated fullerenes for inhibition of LPS heptosyltransferase WaaC.

Fig. 16

Model of a self-assembled SgsE-neoglycoprotein monolayer periodically displaying recombinant E. coli O7 antigens with nanometer-scale precision. Image reconstruction using Cinema 4 is based on a negatively stained preparation of the S-layer protein self-assembled in solution and on the pdb data of the glycans generated with Sweet at http://www.glycosciences.de/ (adapted from ref. , Wiley-VCH Weinheim).

Fig. 17

Synthetic lipids with TLR4-modulating activity.

Fig. 18

Gold nanoparticles bearing Galβ(1-4)Glcβ(1-6)[Galβ(1-4)]GlcNAcβ(1- (repeating units of S. pneumoniae type 14 capsular polysaccharide), T-helper ovalbumin (OVA) peptide OVA_323-239 and d-glucose as carriers for synthetic carbohydrate-based vaccines.