title: Tetra- versus Pentavalent Inhibitors of Cholera Toxin.
abstract: The five B-subunits (CTB5) of the Vibrio cholerae (cholera) toxin can bind to the intestinal cell surface so the entire AB5 toxin can enter the cell. Simultaneous binding can occur on more than one of the monosialotetrahexosylganglioside (GM1) units present on the cell surface. Such simultaneous binding arising from the toxins multivalency is believed to enhance its affinity. Thus, blocking the initial attachment of the toxin to the cell surface using inhibitors with GM1 subunits has the potential to stop the disease. Previously we showed that tetravalent GM1 molecules were sub-nanomolar inhibitors of CTB5. In this study, we synthesized a pentavalent version and compared the binding and potency of penta- and tetravalent cholera toxin inhibitors, based on the same scaffold, for the first time. The pentavalent geometry did not yield major benefits over the tetravalent species, but it was still a strong inhibitor, and no major steric clashes occurred when binding the toxin. Thus, systems which can adopt more geometries, such as those described here, can be equally potent, and this may possibly be due to their ability to form higher-order structures or simply due to more statistical options for binding.
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Ou
authors.initials: O
authors.lastname: Fu
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Aliaksei V
authors.initials: AV
authors.lastname: Pukin
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: H C Quarles
authors.initials: HC
authors.lastname: van Ufford
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands ; School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds Leeds, LS2 9JT, United Kingdom.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Branson
authors.affiliation: Van 't Hoff Laboratory for Physical and Colloid Chemistry, Debye Institute for Nanomaterials Science, Utrecht University Padualaan 8, 3584 CH, Utrecht, The Netherlands.
authors.forename: Dominique M E
authors.initials: DM
authors.lastname: Thies-Weesie
authors.affiliation: School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds Leeds, LS2 9JT, United Kingdom.
authors.forename: W Bruce
authors.initials: WB
authors.lastname: Turnbull
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University PO Box 80.165, 3508 TD, Utrecht, The Netherlands.
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Visser
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht University P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
authors.forename: Roland J
authors.initials: RJ
authors.lastname: Pieters
keywords: CuAAC click conjugation; GM1 oligosaccharide; cholera toxin; glycodendrimers; multivalency