Synthetic Self-Assembling Clostridial Chimera for Modulation of Sensory Functions

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• 作者：Enrico Ferrari ; Chunjing Gu ; Dhevahi Niranjan ; Laura Restani ; Christine Rasetti-Escargueil ; Ilona Obara ; Sandrine M. Geranton ; Jason Arsenault ; Tom A. Goetze ; Callista B. Harper ; Tam H. Nguyen ; Elizabeth Maywood ; John O鈥橞rien ; Giampietro Schiavo ; Daniel W. Wheeler ; Frederic A. Meunier ; Michael Hastings ; J. Michael Edwardson ; Dorothea Sesardic ; Matteo Caleo ; Stephen P. Hunt ; Bazbek Davletov
• 刊名：Bioconjugate Chemistry
• 出版年：2013
• 出版时间：October 16, 2013
• 年：2013
• 卷：24
• 期：10
• 页码：1750-1759
• 全文大小：469K
• 年卷期：v.24,no.10(October 16, 2013)
• ISSN：1520-4812

文摘

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 鈥榩rotein stapling鈥?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.