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通过本国状态稳定有效抑制TDP-43聚合

Lixin Yang¹, Yllza Jasiqi¹, Agnès Zettor²

¹Laboratory of Molecular and Chemical Biology of Neurodegeneration, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Rte Cantonale, 1015, Lausanne, Switzerland.

Angewandte Chemie (International ed. in English)

|November 10, 2023

概括

用43kDa (TDP-43) 稳定交换性反应DNA结合蛋白的原生状态,为神经退行性疾病提供了一个新的治疗策略. 这项研究表明,TDP-43原生状态稳定有效地防止聚合,为新药发现铺平了道路.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
生物化学生物化学

背景情况:

TDP-43聚合是神经退行性疾病的标志,如ALS.
目前的战略重点是防止TDP-43错误折叠和聚合.
针对TDP-43的原生状态是一个有前途的治疗途径.

研究的目的:

作为一种疾病修饰策略,为TDP-43的原始状态稳定提供概念证明.
设计和验证稳定其原生单体形式的TDP-43变体和配体.
开发一种高通量选试验,用于识别TDP-43原生状态稳定剂.

主要方法:

利用冷电磁结构来设计破坏聚合的C端TDP-43替代物 (S333D/S342D).
评估了替代物和寡核酸联体结合对TDP-43稳定性和聚合的影响.
开发了一种可控聚合系统,用于高通量选试验.

主要成果:

设计的TDP-43替代物 (S333D/S342D),可以稳定单体形式而不改变生理性质.
证明原生寡核酸连体稳定单体TDP-43,防止纤维化和相分离.
建立了一种功能性高通量选试验,用于识别TDP-43原生状态稳定剂.

结论:

对于TDP-43蛋白病变来说,TDP-43原始状态稳定是一种可行且有效的治疗策略.
可以针对TDP-43的不同结构域进行治疗干预.
这项工作为发现用于治疗与TDP-43.3相关的神经退行性疾病的新药提供了一个平台.

关键词:

聚合聚合是一种聚合.原生国家稳定化有氧核酸类的在TDP-43中使用.

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