Open AccessTetra‐ versus Pentavalent Inhibitors of Cholera Toxin
Author(s) -
Fu Ou,
Pukin Aliaksei V.,
van Ufford H. C. Quarles,
Branson Thomas R.,
ThiesWeesie Dominique M. E.,
Turnbull W. Bruce,
Visser Gerben M.,
Pieters Roland J.
Publication year - 2015
Publication title -
chemistryopen
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.644
H-Index - 29
ISSN - 2191-1363
DOI - 10.1002/open.201500006
Subject(s) - cholera toxin , vibrio cholerae , toxin , chemistry , steric effects , binding site , biophysics , cholera , stereochemistry , cell , biochemistry , biology , bacteria , microbiology and biotechnology , genetics
The five B‐subunits (CTB 5 ) of the Vibrio cholerae (cholera) toxin can bind to the intestinal cell surface so the entire AB 5 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 CTB 5 . 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.