Abstract
Numerous biological processes involve the recognition of a specific pattern of binding sites on a target protein or surface. Although ligands displayed by disordered scaffolds form stochastic rather than specific patterns, theoretical models predict that recognition will occur between patterns that are characterized by similar or “matched” statistics1,2,3,4. Endowing synthetic biomimetic structures with statistical pattern matching capabilities may improve the specificity of sensors and resolution of separation processes5. We demonstrate that statistical pattern matching enhances the potency of polyvalent therapeutics. We functionalized liposomes with an inhibitory peptide at different densities and observed a transition in potency at an interpeptide separation that matches the distance between ligand-binding sites on the heptameric component of anthrax toxin. Pattern-matched polyvalent liposomes inhibited anthrax toxin in vitro at concentrations four orders of magnitude lower than the corresponding monovalent peptide, and neutralized this toxin in vivo. Statistical pattern matching also enhanced the potency of polyvalent inhibitors of cholera toxin. This facile strategy should be broadly applicable to the detection and neutralization of toxins and pathogens.
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Acknowledgements
This work was supported by National Institutes of Health grant UO1 AI056546. J.M. holds the Canada Research Chair in Bacterial Pathogenesis.
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Supplementary information
Supplementary Fig. 1
Preincubation of peptide-functionalized liposomes with [PA63]7 decreases the measured IC50. (PDF 64 kb)
Supplementary Fig. 2
Influence of ligand density and preincubation time on the inhibitory potency of DSPC-based galactose-functionalized liposomes (PDF 68 kb)
Supplementary Table 1
Estimated average inter-ligand separations for DSPC-based and DOPC-based liposomes as a function of ligand density (PDF 39 kb)
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Rai, P., Padala, C., Poon, V. et al. Statistical pattern matching facilitates the design of polyvalent inhibitors of anthrax and cholera toxins. Nat Biotechnol 24, 582–586 (2006). https://doi.org/10.1038/nbt1204
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DOI: https://doi.org/10.1038/nbt1204
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