发现了一种天然小分子抑制剂,用于用于治疗缺血性中风的新目标STAT5A
Jiping Liao1, Xinnan Li1, Cheng Fan1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Journal of medicinal chemistry
|October 18, 2025
概括
研究人员发现了一种天然化合物 (±) -2,可以保护大脑细胞免受缺血性中风 (IS) 损伤. 它通过准STAT5A,一种以前与神经保护无关的蛋白质来起作用,为IS提供了一个新的治疗途径.
科学领域:
- 自然产品化学 自然产品化学
- 神经药理学神经药理学
- 分子生物学分子生物学
背景情况:
- 信号传感器和转录5A (STAT5A) 激活器在癌症中的作用已确立,但其神经保护潜力,特别是在缺血性中风 (IS) 中,尚不清楚.
- 缺血性中风 (IS) 是导致死亡和残疾的主要原因,需要新的治疗点和候选药物.
研究的目的:
- 为了探索从Heterosmilax yunnanensis*中分离出来的stilbenoid二元体的神经保护作用.
- 为了确定已识别的神经保护性化合物的分子标和作用机制.
- 评估一种新型天然化合物作为抗IS治疗剂的潜力.
主要方法:
- 使用HPLC-DAD-HRESIMS.16种stilbenoid二元体的隔离和结构阐明.
- 在MCAO模型中对神经保护作用的体内评估.
- 活性化合物的立体和区域选择性合成 (±) -2.
- 化学蛋白质组学来识别直接的细胞目标.
- 涉及蛋白质结合和酸化抑制的机制研究.
主要成果:
- 在MCAO模型中,化合物 (±) - 2显著降低了神经元缺血损伤.
- 确定STAT5A是 (±) -2的直接细胞标.
- (±) - 2通过与Lys644结合来抑制STAT5A酸化,从而产生抗IS作用.
- 结构-活性关系 (SAR) 分析强调了A环上基基的重要性.
结论:
- STAT5A代表了一种针对缺血性中风的新型治疗点.
- (±) - 2 是第一个被发现能针对STAT5A产生抗IS作用的天然化合物.
- 这项研究为IS治疗提供了一个有希望的天然药物候选者.
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