We have been investigating a biomimetic approach to drug design based on the concept of polyvalency – the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another. Nature makes extensive use of polyvalency as a means of strengthening inherently weak binding interactions, and we are applying this context to enhance the potency of ligands that bind to pathogens or bacterial toxins. In the present work, we will describe the rational design of heptavalent molecules that bind to the heptameric subunit of anthrax toxin. To match the symmetry of the target, these molecules are composed of a β-cyclodextrin core attached to seven peptides through flexible polyethylene glycol linkers. These well-defined inhibitors are at least 4 orders of magnitude more potent than the corresponding monovalent peptides, in vitro. Optimal potency of the heptavalent molecules, designed with a structure-based approach, is seen when the size and geometry of the resulting ligands match the spatial distribution of binding sites on the target protein. These heptavalent inhibitors are also effective in neutralizing anthrax toxin in vivo and their biodegradability and non-immunogenicity makes them attractive for designing inhibitors against a variety of toxins and pathogens.

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