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确定用于治疗神经退行性疾病的新型小分子伴侣激活剂

Anita K Ho¹, Fiona Jeganathan², Magda Bictash²

¹York Biomedical Research Institute, Department of Biology, University of York, Wentworth Way, York YO10 5DD, UK.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

|April 16, 2025

概括

研究人员开发了一种药物选试验,以激活热冲击因子1 (HSF1),这是细胞蛋白质稳态的关键调节器,用于对抗神经退行性疾病. 该研究确定了氧butazone作为一个有前途的化合物,可以减少有毒的蛋白质聚合物,而不会引起细胞应激.

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
药物发现药物发现药物发现

背景情况:

异常蛋白质聚合物是神经退行性疾病的病理标志,有助于细胞毒性.
热冲击蛋白 (HSP) 对于维持细胞蛋白质平衡至关重要,并且可以向有毒蛋白质积累.
激活HSP提供了一种治疗策略,通过清除TDP-43,和粉样蛋白等异常蛋白来缓解神经退行性疾病.

研究的目的:

开发一种药物选试验,用于识别激活热冲击因子1 (HSF1) 的化合物,这是HSP的主要调节器.
选破坏HSF1-HSP90相互作用的化合物,从而释放HSF1进行激活.
通过针对异常蛋白质聚合来确定神经退行性疾病的新型治疗候选者.

主要方法:

开发和验证一个纳米BRET试验量化HSF1-HSP90相互作用在活细胞.
使用开发的测试方法对2000个化合物库进行选.
在神经退行细胞模型中对命中化合物的功能研究.

主要成果:

纳米BRET试验成功监测和量化了HSF1-HSP90相互作用.
查发现了10种有效化合物,包括两种已知的HSP90抑制剂.
氧butazone (OPB),一个新鲜的打击,显著减少不溶性TDP-43在细胞模型中的积累,而不会诱导毒性.

结论:

该研究提出了一个可行的药物发现策略,针对神经退行性疾病中异常蛋白质聚合.
开发的试验有效地识别了激活HSF1.1的化合物.
氧布塔在治疗特征为TDP-43聚合的神经退行性疾病方面显示出治疗潜力.

关键词:

陪伴者 (Chaperones) 是指一个陪伴者.药物查是指对药物进行查.在HSF1中,它是HSF1.神经退行性疾病是一种神经退行性疾病.在TDP-43中使用.

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