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Wiley, Angewandte Chemie, 32(126), p. 8394-8394, 2014

DOI: 10.1002/ange.201405672

Wiley, Angewandte Chemie, 32(126), p. 8463-8467, 2014

DOI: 10.1002/ange.201404397

Wiley, Angewandte Chemie International Edition, 32(53), p. 8323-8327, 2014

DOI: 10.1002/anie.201404397

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A Protein-Based Pentavalent Inhibitor of the Cholera Toxin B-Subunit

Journal article published in 2014 by Thomas R. Branson, Tom E. McAllister, Jaime Garcia-Hartjes, Martin A. Fascione, James F. Ross, Stuart L. Warriner ORCID, Tom Wennekes ORCID, Han Zuilhof, W. Bruce Turnbull
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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 (IC50) of 104 pM 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. Cholera versus cholera: The inhibition of multivalent protein/carbohydrate interactions between toxins and glycolipids in cell membranes can prevent the toxins from entering cells. The site‐specific modification of a protein scaffold, matched in both size and valency to the target toxin, led to a multivalent inhibitor with an IC50 value of 104 pM for the cholera toxin B‐subunit.