Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin |
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| Authors: | Sanket Patke Mohan Boggara Ronak Maheshwari Sunit K. Srivastava Manish Arha Marc Douaisi Jacob T. Martin Ian B. Harvey Matthew Brier Tania Rosen Jeremy Mogridge Prof. Ravi S. Kane |
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| Affiliation: | 1. Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180 (USA);2. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180 (USA);3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada) |
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| Abstract: | The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure–activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide‐based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin‐binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells. |
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| Keywords: | anthrax toxin multivalency periodic polypeptides protein engineering structure– activity relationships |
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