在in silico转录组屏幕中识别了表皮生长因子受体抑制剂作为噪音引起的听力损失的治疗方法
Sarath Vijayakumar1, Joseph A DiGuiseppi1, Parinaz Jila Dabestani1
1Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE 68178, USA.
Science advances
|June 19, 2024
概括
研究人员使用计算机查确定了噪音引起的听力损失 (NIHL) 的潜在药物. 表皮生长因子受体 (EGFR) 抑制剂,如 zorifertinib,在动物模型中显示出对NIHL的保护有希望.
科学领域:
- 耳鼻喉科 耳鼻喉科 耳鼻喉科
- 药理学 药理学是指药理学的学科.
- 计算生物学 计算生物学
背景情况:
- 噪音引起的听力损失 (NIHL) 是一种普遍的感觉神经损伤,没有FDA批准的药理疗法.
- 目前NIHL的查模型缺乏效率,需要创新的方法.
研究的目的:
- 通过基于in silico转录组的药物选方法,确定NIHL的潜在治疗剂.
- 在临床前NIHL模型中研究已识别的化合物的疗效,特别是表皮生长因子受体 (EGFR) 抑制剂.
主要方法:
- 采用基于体转录基因的药物选方法来确定潜在的NIHL治疗方法.
- 在斑马鱼和小鼠模型中验证了已识别的化合物,包括阿法替尼和佐里弗蒂尼布 (EGFR抑制剂).
- 在小鼠中进行了分子研究和斑马鱼 (EGFR knockout/morpholino) 的遗传分析,以证实EGFR的作用和药物疗效.
主要成果:
- 确定了22种生物途径和64种潜在的NIHL小分子治疗方法.
- 在斑马鱼和小鼠模型中,阿法替尼和佐黎费尔替尼显示出对NIHL的保护作用.
- 证实了EGFR在NIHL和 zorifertinib的保护机制中的关键作用,在口服后具有有利的药理动力学.
- 佐里弗蒂尼布与AZD5438结合,显示出对斑马鱼的NIHL的协同预防.
结论:
- 基于in silico转录组的药物查是缺乏有效模型的疾病的可行方法.
- EGFR抑制剂,如 zorifertinib,代表了NIHL的有前途的治疗候选者.
- 需要进一步的临床试验来评估EGFR抑制剂在NIHL治疗中的治疗潜力.
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