• Biochem. Biophys. Res. Commun. · Feb 2011

    Neuronal targeting, internalization, and biological activity of a recombinant atoxic derivative of botulinum neurotoxin A.

    • Sabine Pellett, William H Tepp, Larry H Stanker, Philip A Band, Eric A Johnson, and Konstantin Ichtchenko.
    • Department of Bacteriology, University of Wisconsin-Madison, 1550 Linden Dr, Madison, WI 53706, United States.
    • Biochem. Biophys. Res. Commun. 2011 Feb 25; 405 (4): 673-7.

    AbstractNon-toxic derivatives of botulinum neurotoxin A (BoNT/A) have potential use as neuron-targeting delivery vehicles, and as reagents to study intracellular trafficking. We have designed and expressed an atoxic derivative of BoNT/A (BoNT/A ad) as a full-length 150 kDa molecule consisting of a 50 kDa light chain (LC) and a 100 kDa heavy chain (HC) joined by a disulfide bond and rendered atoxic through the introduction of metalloprotease-inactivating point mutations in the light chain. Studies in neuronal cultures demonstrated that BoNT/A ad cannot cleave synaptosomal-associated protein 25 (SNAP25), the substrate of wt BoNT/A, and that it effectively competes with wt BoNT/A for binding to endogenous neuronal receptors. In vitro and in vivo studies indicate accumulation of BoNT/A ad at the neuromuscular junction of the mouse diaphragm. Immunoprecipitation studies indicate that the LC of BoNT/A ad forms a complex with SNAP25 present in the neuronal cytosolic fraction, demonstrating that the atoxic LC retains the SNAP25 binding capability of the wt toxin. Toxicity of BoNT/A ad was found to be reduced approximately 100,000-fold relative to wt BoNT/A.Copyright © 2011 Elsevier Inc. All rights reserved.

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