We demonstrate that interactions between multimeric receptors and multivalent ligands are dramatically enhanced by recruiting a complementary templating receptor such as an endogenous multimeric protein but only when individual ligands are attached to a polymer as preorganized, covalent, heterobifunctional pairs. This effect cannot be replicated by a multivalent ligand if the same recognition elements are independently arrayed on the scaffold. Application of this principle offers an approach to create highavidity inhibitors for multimeric receptors. Judicious selection of the ligand that engages the templating protein allows appropriate effector function to be incorporated in the polymeric construct, thereby providing an opportunity for therapeutic applications. The power of this approach is exemplified by the design of exceptionally potent Escherichia coli Shiga toxin antagonists that protect transgenic mice that constitutively express a human pentraxin, serum amyloid P component.heterobifunctional ligand ͉ multivalency ͉ Shiga toxin

Background: E. coli Shiga like toxin type 2 (Stx2a) is responsible for serious clinical outcomes. Results: The crystal structure of Stx2a with bound disaccharide was solved and used to design a potent toxin inhibitor. Conclusion:The primary binding site of Stx2a is able to accommodate extended structural elements. Significance: Knowledge of the toxin binding site can guide discovery of therapeutics to treat E. coli food poisoning.

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