Synthetic self-assembling clostridial chimera for modulation of sensory functions.
Synthetic self-assembling clostridial chimera for modulation of sensory functions.
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DOI：
10.1021/bc4003103
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发表时间：
2013-10-16
影响因子：
4.7
通讯作者：
Davletov, Bazbek
中科院分区：
文献类型：
--
作者：
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
梭菌神经毒素可逆地阻断神经元通讯数周和数月。虽然这些蛋白水解神经毒素在临床应用和脑功能研究方面有很大的希望，但它们在神经肌肉接头处的麻痹活性是一个绊脚石。为了将梭菌活性重定向到运动神经元以外的神经元群体，我们使用了一种新的自组装方法将肉毒杆菌A型蛋白酶与破伤风结合结构域（其天然靶向中枢神经元）联合收割机组合。这两个部分分别生产，然后使用新引入的“蛋白质钉合”技术以特定的方式组装。原子力显微镜成像显示哑铃形颗粒，其测量值为23 nm。吻合器嵌合体在大鼠炎性疼痛模型中抑制机械超敏反应，而不引起弛缓性或痉挛性麻痹。此外，合成的梭菌分子能够阻断视觉皮层特定区域的神经元活动。总的来说，我们提供了第一个证据表明，蛋白质钉合技术允许组装不同的蛋白质，产生新的生物医学特性。
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.
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