Carbohydrate inhibitors of cholera toxin

Abstract

Cholera is a diarrheal disease caused by a protein toxin released by Vibrio cholera in the host's intestine. The toxin enters intestinal epithelial cells after binding to specific carbohydrates on the cell surface. Over recent years, considerable effort has been invested in developing inhibitors of toxin adhesion that mimic the carbohydrate ligand, with particular emphasis on exploiting the multivalency of the toxin to enhance activity. In this review we introduce the structural features of the toxin that have guided the design of diverse inhibitors and summarise recent developments in the field.

Keywords: carbohydrate; cholera; multivalency; toxin.

Figure 1

a) Ribbon and b) surface depictions of the cholera toxin: A1₁ domain in light blue; A1₂ domain in dark blue; A1₃ domain in purple; cystine disulfide in orange; A2 peptide in green and B-subunit in red. Figure prepared using the PyMOL programme from Protein Data Bank file 1XTC.pdb.

Figure 2

a) Structure of the cholera toxin showing the location of its carbohydrate binding sites and the structures of the Lewis-y and Ganglioside GM₁ ligands; A-subunit (blue), B-subunit (red) and the A2 peptide linker (green). b) Bottom face of the toxin showing the symmetry of the B-subunit and the A2 peptide linker emerging through the central channel. c) Close-up view of the two sugar binding sites. Figure prepared using the PyMOL programme from Protein Data Bank files 1XTC.pdb, 3CHB.pdb and 3EFX.pdb.

Figure 3

Bernardi and co-workers’ designed oligosaccharide mimetics of GM₁.

Figure 4

Structure of monomeric ligands. X = amino acid residues, aminoalkyl, 1,2,3 triazoles; n = 1, 2; R = H, Me, R' = OH, NHAc.

Figure 5

Bivalent inhibitor designed and synthesised by Pickens et al.

Figure 6

Bivalent inhibitor designed and synthesized by Arosio et al.

Figure 7

Bivalent inhibitors designed and synthesised by Leaver and Liu.

Figure 8

Bivalent and tetravalent inhibitor designed and synthesised by Pieters, and Bernardi et al.

Figure 9

Cyclic inhibitors synthesised by Kumar et al. for CT.

Figure 10

The star-shaped inhibitors reported by Fan, Hol and co-workers.

Figure 11

Differently sized cyclic decavalent peptide core designed by Zhang et al.

Figure 12

Calix[5]arene core-based pentavalent inhibitor designed by Garcia-Hartjes et al.

Figure 13

Corannulene core-based pentavalent inhibitor designed by Mattarella et al.

Figure 14

Pentavalent inhibitor designed by Pieters and co-workers.

Figure 15

Neoglycoprotein inhibitor based on a non-binding mutant of CTB.

Figure 16

Octavalent inhibitor designed by Pieters, Bernardi and co-workers.

Figure 17

Hetero-bifunctional inhibitor designed by Bundle and co-workers.

Figure 18

Glycopolymers with exchangeable sugar ligands and variable length linkers.