Multivalency at Work

Cholera and travellers’ diarrhoea are caused by a two-step process, by which protein toxins displaying a pentavalent binding domain interact with oligosaccharides of ganglioside GM1 on the periphery of human abdominal epithelial cells, and then followed by the injection of the toxic subunit into the cell. The cholera toxin has five GM1 binding sites arranged on the same face of the protein, which make them ideal candidates for multivalent inhibition. To this end a complex molecular assembly containing five GM1 linked to a calix[5]arene scaffold has been synthesized.

When evaluated by an inhibition assay the multivalent glycoalixarene achieved a picomolar inhibition potency for the cholera toxin binding domain. This represents a significant multivalency effect, with a relative inhibitory potency of 100 000 compared to a monovalent GM1os derivative, making GM1os-calix[5]arene one of the most potent known Cholera Toxin inhibitors.

Reference : Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene, J. Garcia-Hartjes, S. Bernardi, C.A. G. M. Weijers, T. Wennekes, M. Gilbert, F. Sansone, A. Casnati & H. Zuilhof*, Org. Biomol. Chem., 2013, Advance Article, DOI : 10.1039/C3OB40515J