Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape,RSC Chemical Biology

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Direct targeting of TDP-43, from small molecules to biologics: the therapeutic landscape
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2021-06-21 , DOI: 10.1039/d1cb00110h
Liberty Francois-Moutal _{1,

2} , David Donald Scott _{1,

2} , May Khanna _{1,

2,

3}

Affiliation

Tar DNA binding (TDP)-43 proteinopathy, typically described as cytoplasmic accumulation of highly modified and misfolded TDP-43 molecules, is characteristic of several neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). TDP-43 proposed proteinopathies include homeostatic imbalance between nuclear and cytoplasmic localization, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and an increase in protein truncation of cytoplasmic TDP-43. Given the therapeutic interest of targeting TDP-43, this review focuses on the current landscape of strategies, ranging from biologics to small molecules, that directly target TDP-43. Antibodies, peptides and compounds have been designed or found to recognize specific TDP-43 sequences but alleviate TDP-43 toxicity through different mechanisms. While two antibodies described here were able to induce degradation of pathological TDP-43, the peptides and small molecules were primarily designed to reduce aggregation of TDP-43. Furthermore, we discuss promising emerging therapeutic targets.

中文翻译：

直接靶向 TDP-43，从小分子到生物制剂：治疗前景

Tar DNA 结合 (TDP)-43 蛋白病通常被描述为高度修饰和错误折叠的 TDP-43 分子在细胞质中积聚，是多种神经退行性疾病的特征，例如肌萎缩性脊髓侧索硬化症 (ALS) 和边缘主导的年龄相关 TDP-43 脑病（晚的）。TDP-43 提出的蛋白质病包括核和细胞质定位之间的稳态失衡、泛素化和过度磷酸化 TDP-43 的聚集以及细胞质 TDP-43 蛋白质截短的增加。鉴于靶向 TDP-43 的治疗兴趣，本综述重点关注直接靶向 TDP-43 的策略（从生物制剂到小分子）的当前前景。抗体、肽和化合物已被设计或发现可识别特定的 TDP-43 序列，但通过不同的机制减轻 TDP-43 毒性。虽然此处描述的两种抗体能够诱导病理性 TDP-43 降解，但肽和小分子主要设计用于减少 TDP-43 的聚集。此外，我们讨论了有前景的新兴治疗靶点。

更新日期：2021-06-28

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