Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands

Pavel I. Kitov, Joanna M. Sadowska, George Mulvey, Glen D. Armstrong, Hong Ling, Navraj S. Pannu, Randy J. Read and David R. Bundle
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Pavel I. Kitov: University of Alberta
Joanna M. Sadowska: University of Alberta
George Mulvey: University of Alberta
Glen D. Armstrong: University of Alberta
Hong Ling: University of Alberta
Navraj S. Pannu: Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, University of Cambridge
Randy J. Read: University of Alberta
David R. Bundle: University of Alberta

Nature, 2000, vol. 403, issue 6770, 669-672

Abstract: Abstract The diseases caused by Shiga and cholera toxins account for the loss of millions of lives each year1. Both belong to the clinically significant subset of bacterial AB5 toxins consisting of an enzymatically active A subunit that gains entry to susceptible mammalian cells after oligosaccharide recognition by the B5 homopentamer2,3. Therapies might target the obligatory oligosaccharide–toxin recognition event4, but the low intrinsic affinity of carbohydrate–protein interactions hampers the development of low-molecular-weight inhibitors5. The toxins circumvent low affinity by binding simultaneously to five or more cell-surface carbohydrates6. Here we demonstrate the use of the crystal structure of the B5 subunit of Escherichia coli O157:H7 Shiga-like toxin I (SLT-I) in complex with an analogue of its carbohydrate receptor6 to design an oligovalent, water-soluble carbohydrate ligand (named STARFISH), with subnanomolar inhibitory activity. The in vitro inhibitory activity is 1–10-million-fold higher than that of univalent ligands and is by far the highest molar activity of any inhibitor yet reported for Shiga-like toxins I and II. Crystallography of the STARFISH/Shiga-like toxin I complex explains this activity. Two trisaccharide receptors at the tips of each of five spacer arms simultaneously engage all five B subunits of two toxin molecules.

Date: 2000
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DOI: 10.1038/35001095

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