Synthetic self-assembling clostridial chimera for modulation of sensory functions

Ferrari, E.; 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.; Davletov, B.

doi:10.1021/bc4003103

Synthetic self-assembling clostridial chimera for modulation of sensory functions

Ferrari, E.; 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.; Davletov, B.

Authors

E. Ferrari

C. Gu

D. Niranjan

L. Restani

C. Rasetti-Escargueil

I. Obara

S.M. Geranton

J. Arsenault

T.A. Goetze

C.B. Harper

T.H. Nguyen

E. Maywood

J. O'Brien

G. Schiavo

D.W. Wheeler

F.A. Meunier

M. Hastings

J.M. Edwardson

D. Sesardic

M. Caleo

S.P. Hunt

B. Davletov

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 ∼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.

Citation

Ferrari, E., Gu, C., Niranjan, D., Restani, L., Rasetti-Escargueil, C., Obara, I., …Davletov, B. (2013). Synthetic self-assembling clostridial chimera for modulation of sensory functions. Bioconjugate Chemistry, 24(10), 1750-1759. https://doi.org/10.1021/bc4003103

Journal Article Type	Article
Online Publication Date	Sep 6, 2013
Publication Date	Oct 16, 2013
Deposit Date	Feb 12, 2014
Publicly Available Date	May 4, 2016
Journal	Bioconjugate Chemistry
Print ISSN	1043-1802
Electronic ISSN	1520-4812
Publisher	American Chemical Society
Peer Reviewed	Peer Reviewed
Volume	24
Issue	10
Pages	1750-1759
DOI	https://doi.org/10.1021/bc4003103