title: Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene.
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 100,000 compared to a monovalent GM1os derivative, making GM1os-calix[5]arene one of the most potent known CTB inhibitors.
authors.affiliation: Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands.
authors.forename: Jaime
authors.initials: J
authors.lastname: Garcia-Hartjes
authors.forename: Silvia
authors.initials: S
authors.lastname: Bernardi
authors.forename: Carel A G M
authors.initials: CA
authors.lastname: Weijers
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.forename: Michel
authors.initials: M
authors.lastname: Gilbert
authors.forename: Francesco
authors.initials: F
authors.lastname: Sansone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Casnati
authors.forename: Han
authors.initials: H
authors.lastname: Zuilhof
mesh_terms: D000992:Antitoxins / Q000737:chemistry* / Q000494:pharmacology*; D047250:Calixarenes / Q000737:chemistry* / Q000494:pharmacology*; D002771:Cholera / Q000188:drug therapy / Q000382:microbiology; D002772:Cholera Toxin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D014734:Vibrio cholerae / Q000187:drug effects / Q000201:enzymology
chemical_list: D000992:Antitoxins; D047250:Calixarenes; D005677:G(M1) Ganglioside; D002772:Cholera Toxin