title: A protein-based pentavalent inhibitor of the cholera toxin B-subunit.
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.
authors.affiliation: School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT (UK).
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Branson
authors.forename: Tom E
authors.initials: TE
authors.lastname: McAllister
authors.forename: Jaime
authors.initials: J
authors.lastname: Garcia-Hartjes
authors.forename: Martin A
authors.initials: MA
authors.lastname: Fascione
authors.forename: James F
authors.initials: JF
authors.lastname: Ross
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Warriner
authors.forename: Tom
authors.initials: T
authors.lastname: Wennekes
authors.forename: Han
authors.initials: H
authors.lastname: Zuilhof
authors.forename: W Bruce
authors.initials: WB
authors.lastname: Turnbull
mesh_terms: D001419:Bacteria / Q000378:metabolism*; D001665:Binding Sites; D002241:Carbohydrates; D002772:Cholera Toxin / Q000737:chemistry*; D006023:Glycoproteins; D008958:Models, Molecular; D011506:Proteins
chemical_list: D002241:Carbohydrates; D006023:Glycoproteins; D011506:Proteins; D002772:Cholera Toxin
keywords: carbohydrates; glycoproteins; multivalency; protein modifications; protein structures