Fu, O, Pukin, AV, Quarles van Ufford, HC et al. (5 more authors) (2015) Tetra- versus Pentavalent Inhibitors of Cholera Toxin. ChemistryOpen, 4 (4). 471 - 477. ISSN 2191-1363
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
Keywords: | Cholera toxin; CuAAC click conjugation; Glycodendrimers; GM1 oligosaccharide; Multivalency |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Funding Information: | Funder Grant number EPSRC EP/G043302/1 Royal Society UF090025 |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Oct 2015 13:24 |
Last Modified: | 15 Oct 2015 13:24 |
Published Version: | http://dx.doi.org/10.1002/open.201500006 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/open.201500006 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:89070 |