New non-paralytic botulinum molecules for the control of pain

用于控制疼痛的新型非麻痹性肉毒杆菌分子

• 批准号: MR/K022539/1
• 负责人: Bazbek Davletov
• 金额: $ 87.39万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK022539%2F1
• 关键词: New; non; paralytic; botulinum; molecules

In both animals and humans life events such as accidents or surgical interventions can lead to uncontrollable pain that can persist long after the original injury. This is chronic pain, the treatment of which is yet to be resolved - 19% of adult Europeans suffer from chronic pain of moderate to severe intensity; less than 60% receive adequate pain relief. New treatments are required but to develop these requires new therapeutic approaches and a better understanding of what goes wrong in the pain pathways resulting in uncontrollable pain. Using the results of our recent research on Botulinum molecules, together with our existing knowledge of pain mechanisms, we will selectively silence pain signals both in pain fibers from the skin and other body tissues as well as in specific nerve cells in the spinal cord. Botulinum molecule is a protein and neurotoxin produced by the bacterium Clostridium botulinum. Botulinum molecule can cause flaccid neuromuscular paralysis, a serious and life-threatening illness in humans and animals. Popularly known by one of its trade names, Botox, it is used for various cosmetic and medical procedures. However we have found a way to separate the paralysing effects of the botulinum molecule from its silencing effects on other neurons. By using this new synthetic chemistry we will target and silence specific populations of neurons reversibly and alleviate chronic pain states.The experiments outlined in this application will allow us to move rapidly towards the clinic and to apply these new Botulinum derivatives to different types of chronic pain. For example it is possible to imagine that a single injection of one of our Botulinum constructs into a painful arthritic joint or over the spinal cord of a patient with bone cancer pain would ameliorate pain without generating numbness or paralysis.

在动物和人类的生活事件，如事故或手术干预可能会导致无法控制的疼痛，可以持续很长时间后，原来的伤害。这是一种慢性疼痛，其治疗方法尚未得到解决- 19%的欧洲成年人患有中度至重度慢性疼痛;不到60%的人得到充分的疼痛缓解。需要新的治疗方法，但要开发这些方法，需要新的治疗方法，并更好地了解疼痛通路中出现的问题，从而导致无法控制的疼痛。利用我们最近对肉毒杆菌分子的研究结果，以及我们对疼痛机制的现有知识，我们将选择性地沉默来自皮肤和其他身体组织的疼痛纤维以及脊髓中特定神经细胞的疼痛信号。肉毒素分子是由肉毒梭菌产生的蛋白质和神经毒素。肉毒杆菌分子可导致松弛性神经肌肉麻痹，这是一种严重的危及人类和动物生命的疾病。它的商品名之一Botox广为人知，它用于各种美容和医疗程序。然而，我们已经找到了一种方法，将肉毒杆菌分子的麻痹作用与其对其他神经元的沉默作用分开。通过使用这种新的合成化学，我们将可逆地靶向和沉默特定的神经元群体，并缓解慢性疼痛状态。本申请中概述的实验将使我们能够迅速走向临床，并将这些新的Botlanol衍生物应用于不同类型的慢性疼痛。例如，可以想象，将我们的一种Botanical构建体单次注射到患有骨癌疼痛的患者的疼痛关节炎关节或脊髓上，将改善疼痛，而不会产生麻木或瘫痪。

项目成果

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine.

• DOI: 10.1007/s13311-020-00967-7
• 发表时间: 2021-01
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Andreou AP;Leese C;Greco R;Demartini C;Corrie E;Simsek D;Zanaboni A;Koroleva K;Lloyd JO;Lambru G;Doran C;Gafurov O;Seward E;Giniatullin R;Tassorelli C;Davletov B
• 通讯作者: Davletov B

Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells.

• DOI: 10.1111/jnc.12645
• 发表时间: 2014-06
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Arsenault J;Cuijpers SA;Ferrari E;Niranjan D;Rust A;Leese C;O'Brien JA;Binz T;Davletov B
• 通讯作者: Davletov B

Synthetic self-assembling clostridial chimera for modulation of sensory functions.

• DOI: 10.1021/bc4003103
• 发表时间: 2013-10-16
• 期刊: BIOCONJUGATE CHEMISTRY
• 影响因子: 4.7
• 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
• 通讯作者: Davletov, Bazbek

Double-binding botulinum molecule with reduced muscle paralysis: Evaluation in in vitro and in vivo models of migraine

减少肌肉麻痹的双结合肉毒杆菌分子：偏头痛体外和体内模型的评估

• DOI: 10.1016/j.toxicon.2020.11.350
• 发表时间: 2021
• 期刊: Toxicon
• 影响因子: 2.8
• 作者: Andreou A

Unexpected transcellular protein crossover occurs during canonical DNA transfection.

在规范DNA转染期间发生意外的跨细胞蛋白交叉。

• DOI: 10.1002/jcb.24884
• 发表时间: 2014-12
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Arsenault, Jason;Cuijpers, Sabine A. G.;Niranjan, Dhevahi;Davletov, Bazbek
• 通讯作者: Davletov, Bazbek