Synthetic self-assembling clostridial chimera for modulation of sensory functions

Ferrari, Enrico, Gu, Chunjing, Niranjan, Dhevahi, Restani, Laura, Rasetti-Escargueil, Christine, Obara, Ilona, Geranton, Sandrine M., Arsenault, Jason, Goetze, Tom A., Harper, Callista B., Nguyen, Tam H., Maywood, Elizabeth, O'Brien, John, Schiavo, Giampietro, Wheeler, Daniel W., Meunier, Frederic A., Hastings, Michael, Edwardson, J. Michael, Sesardic, Dorothea, Caleo, Matteo, Hunt, Stephen P. and Davletov, Bazbek (2013) Synthetic self-assembling clostridial chimera for modulation of sensory functions. Bioconjugate Chemistry, 24 10: 1750-1759. doi:10.1021/bc4003103


Author Ferrari, Enrico
Gu, Chunjing
Niranjan, Dhevahi
Restani, Laura
Rasetti-Escargueil, Christine
Obara, Ilona
Geranton, Sandrine M.
Arsenault, Jason
Goetze, Tom A.
Harper, Callista B.
Nguyen, Tam H.
Maywood, Elizabeth
O'Brien, John
Schiavo, Giampietro
Wheeler, Daniel W.
Meunier, Frederic A.
Hastings, Michael
Edwardson, J. Michael
Sesardic, Dorothea
Caleo, Matteo
Hunt, Stephen P.
Davletov, Bazbek
Title Synthetic self-assembling clostridial chimera for modulation of sensory functions
Journal name Bioconjugate Chemistry   Check publisher's open access policy
ISSN 1043-1802
1520-4812
Publication date 2013-10-01
Year available 2013
Sub-type Article (original research)
DOI 10.1021/bc4003103
Open Access Status Not yet assessed
Volume 24
Issue 10
Start page 1750
End page 1759
Total pages 10
Place of publication Washington, DC United States
Publisher American Chemical Society
Language eng
Abstract 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 similar to 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.
Keyword Ocular Dominance Plasticity
Botulinum Neurotoxins
Anterograde Transport
Preventive Treatment
Hippocampal neurons
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID U10578791
089125/Z/09/Z
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
 
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