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

T.R. Branson, T.E. McAllister, J. Garcia Hartjes, M.A. Fascione, J.F. Ross, S.L. Warriner, T. Wennekes, H. Zuilhof, W.B. Turnbull

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)8323-8327
JournalAngewandte Chemie-International Edition
Issue number32
Publication statusPublished - 2014


  • isothermal titration calorimetry
  • heat-labile enterotoxin
  • escherichia-coli
  • receptor-binding
  • multivalent scaffolds
  • vibrio-cholerae
  • ligands
  • gm1
  • ganglioside
  • design


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