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

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Abstract

Cholera toxin (CT), the causative agent of cholera, displays a pentavalent binding domain that targets the oligosaccharide of ganglioside GM1 (GM1os) on the periphery of human abdominal epithelial cells. Here, we report the first GM1os-based CT inhibitor that matches the valency of the CT binding domain (CTB). This pentavalent inhibitor contains five GM1os moieties linked to a calix[5]arene scaffold. When evaluated by an inhibition assay, it achieved a picomolar inhibition potency (IC50 = 450 pM) for CTB. This represents a significant multivalency effect, with a relative inhibitory potency of 100000 compared to a monovalent GM1os derivative, making GM1os-calix[5]arene one of the most potent known CTB inhibitors.
Original languageEnglish
Pages (from-to)4340-4349
JournalOrganic & Biomolecular Chemistry
Volume11
DOIs
Publication statusPublished - 2013

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Keywords

  • heat-labile enterotoxin
  • gm1 mimics
  • binding
  • ligand
  • hexamethylenetetramine
  • oligosaccharide
  • recognition
  • affinity
  • crystal
  • design

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