A protein-based pentavalent inhibitor of the Cholera toxin B-subunit

TY - JOUR

T1 - A protein-based pentavalent inhibitor of the Cholera toxin B-subunit

AU - Branson, Thomas R.

AU - McAllister, Tom E.

AU - Garcia-Hartjes, Jaime

AU - Fascione, Martin Anthony

AU - Ross, James F.

AU - Warriner, Stuart L.

AU - Wennekes, Tom

AU - Zuilhof, Hans

AU - Turnbull, Bruce

PY - 2014/8/4

Y1 - 2014/8/4

N2 - 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.

AB - 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.

KW - carbohydrates;glycoproteins;multivalency;protein modifications;protein structures

U2 - 10.1002/anie.201404397

DO - 10.1002/anie.201404397

M3 - Article

SN - 1433-7851

VL - 53

SP - 8323

EP - 8327

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 32

ER -