A Protein‐Based Pentavalent Inhibitor of the Cholera Toxin B‐Subunit |
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| Authors: | Dr Thomas R Branson Dr Tom E McAllister Jaime Garcia‐Hartjes Dr Martin A Fascione Dr James F Ross Dr Stuart L Warriner Dr Tom Wennekes Prof Han Zuilhof Dr W Bruce Turnbull |
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| Affiliation: | 1. School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT (UK);2. Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen (The Netherlands);3. Department of Chemical and Materials Engineering, King Abdulaziz University, Jeddah (Saudi‐Arabia) |
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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. |
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| Keywords: | carbohydrates glycoproteins multivalency protein modifications protein structures |
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