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Optimization of tether length in nonglycosidically linked bivalent ligands that target sites 2 and 1 of a Shiga-like toxin

Lookup NU author(s): Professor Steve Homans


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A series of bivalent ligands for a Shiga-like toxin have been synthesized, their experimentally determined inhibitory activities were compared with a simplified thermodynamic model, and computer simulations were used to predict the optimal tether length in bivalent ligands. The design of the inhibitors exploits the proximity of the C-2‘ hydroxyl groups of two Pk-trisaccharides when bound to two different, neighboring carbohydrate recognizing binding sites located on the surface of Shiga-like toxin. NMR studies of the complex between the toxin and bivalent ligands show that site 2 and site 1 of a single B subunit are simultaneously occupied by a tethered Pk-trisaccharide dimer. A simplified thermodynamic treatment provides the intrinsic affinities and binding energies for the intermolecular and intramolecular association events and permits the deconvolution of the contributions to the relative binding energies for the set of bivalent ligands. Conformational analysis based on MD simulations for bivalent galabioside dimers containing different tethers demonstrated that the calculated local concentrations of the pendant ligand at the second binding site correlate with the experimentally determined relative affinity values of the respective bivalent ligands, thereby providing a predictive method to optimize tether length.

Publication metadata

Author(s): Kitov PI, Shimizu H, Homans SW, Bundle DR

Publication type: Article

Publication status: Published

Journal: Journal of the American Chemical Society

Year: 2003

Volume: 125

Issue: 11

Pages: 3284-3294

ISSN (print): 0002-7863

ISSN (electronic): 1943-2984

Publisher: American Chemical Society


DOI: 10.1021/ja0258529


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