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Article

Synthesis of Potent Inhibitors of Anthrax Toxin Based on Poly-l-Glutamic Acid

Amit Joshi,^† Arundhati Saraph,^† Vincent Poon,^‡ Jeremy Mogridge,*^‡ and Ravi S. Kane*^†

The Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, New York 12180, and Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S1A8, Canada

Bioconjugate Chem., 2006, 17 (5), pp 1265–1269

DOI: 10.1021/bc060042y

Publication Date (Web): August 10, 2006

†

Rensselaer Polytechnic Institute.

‡

University of Toronto.

Corresponding author. R.S.K.: tel (518) 276 2536; fax (518) 276 4030; e-mail kaner@rpi.edu. J.M.: tel (416) 946 8095; fax (416) 978 5959; e-mail jeremy.mogridge@utoronto.ca.

Abstract

We report the synthesis of biodegradable polyvalent inhibitors of anthrax toxin based on poly-l-glutamic acid (PLGA). These biocompatible polyvalent inhibitors are at least 4 orders of magnitude more potent than the corresponding monovalent peptides in vitro and are comparable in potency to polyacrylamide-based inhibitors of anthrax toxin assembly. We have elucidated the influence of peptide density on inhibitory potency and demonstrated that these inhibitory potencies are limited by kinetics, with even higher activities seen when the inhibitors are preincubated with the heptameric receptor-binding subunit of anthrax toxin prior to exposure to cells. These polyvalent inhibitors are also effective at neutralizing anthrax toxin in vivo and represent attractive leads for designing biocompatible anthrax therapeutics.

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