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A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit
Author(s) -
Branson Thomas R.,
McAllister Tom E.,
GarciaHartjes Jaime,
Fascione Martin A.,
Ross James F.,
Warriner Stuart L.,
Wennekes Tom,
Zuilhof Han,
Turnbull W. Bruce
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201404397
Subject(s) - cholera toxin , protein subunit , toxin , chemistry , virology , medicine , biology , microbiology and biotechnology , biochemistry , gene
Protein toxins produced by bacteria are the cause of many life‐threatening diarrheal diseases. Many of these toxins, including cholera toxin (CT), enter the cell by first binding to glycolipids in the cell membrane. Inhibiting these multivalent protein/carbohydrate interactions would prevent the toxin from entering cells and causing diarrhea. Here we demonstrate that the site‐specific modification of a protein scaffold, which is perfectly matched in both size and valency to the target toxin, provides a convenient route to an effective multivalent inhibitor. The resulting pentavalent neoglycoprotein displays an inhibition potency (IC 50 ) of 104 p M for the CT B‐subunit (CTB), which is the most potent pentavalent inhibitor for this target reported thus far. Complexation of the inhibitor and CTB resulted in a protein heterodimer. This inhibition strategy can potentially be applied to many multivalent receptors and also opens up new possibilities for protein assembly strategies.