Synthetic self-assembling clostridial chimera for modulation of sensory functions

Ferrari, Enrico, Gu, C., Niranjan, D. , Restani, L., Rasetti-Escargueil, C., Obara, I., Geranton, S. M., Arsenault, J., Goetze, T. A., Harper, C. B., Nguyen, T. H., Maywood, E., O'Brien, J., Schiavo, G., Wheeler, D. W., Meunier, F. A., Hastings, M., Edwardson, J. M., Sesardic, D., Caleo, M., Hunt, S. P. and Davletov, B. (2013) Synthetic self-assembling clostridial chimera for modulation of sensory functions. Bioconjugate Chemistry, 24 (10). pp. 1750-1759. ISSN 1043-1802

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Clostridial neurotoxins reversibly block neuronal communication for weeks and months. While these proteolytic neurotoxins hold great promise for clinical applications and the investigation of brain function, their paralytic activity at neuromuscular junctions is a stumbling block. To redirect the clostridial activity to neuronal populations other than motor neurons, we used a new self-assembling method to combine the botulinum type A protease with the tetanus binding domain, which natively targets central neurons. The two parts were produced separately and then assembled in a site-specific way using a newly introduced 'protein stapling' technology. Atomic force microscopy imaging revealed dumbbell shaped particles which measure ∼23 nm. The stapled chimera inhibited mechanical hypersensitivity in a rat model of inflammatory pain without causing either flaccid or spastic paralysis. Moreover, the synthetic clostridial molecule was able to block neuronal activity in a defined area of visual cortex. Overall, we provide the first evidence that the protein stapling technology allows assembly of distinct proteins yielding new biomedical properties. © 2013 American Chemical Society.

Keywords:botulinum toxin A, proteinase, recombinant protein, synaptobrevin 2, tetanus toxin, tetanus toxin binding domain, unclassified drug, animal cell, animal experiment, animal model, article, atomic force microscopy, biological activity, brain function, brain slice, cell population, chimera, circadian rhythm, Clostridium tetani, confocal microscopy, controlled study, flaccid paralysis, hippocampal neuronal culture, male, motoneuron, mouse, nerve cell culture, neuromuscular synapse, nonhuman, pain, particle size, rat, restriction site, sensory analysis, spastic paresis, spinal ganglion, suprachiasmatic nucleus, visual cortex
Subjects:C Biological Sciences > C720 Biological Chemistry
Divisions:College of Science > School of Life Sciences
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ID Code:13412
Deposited On:21 Feb 2014 12:26

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