小分子FICD抑制剂抑制内源性和病理性FICD介导蛋白质AMPylation
Bhaskar K Chatterjee1, Maroof Alam2, Arghya Chakravorty3
1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
bioRxiv : the preprint server for biology
|July 29, 2024
概括
研究人员确定了两种小分子,C22和C73,它们抑制了FICD (FLCN相互作用蛋白D) 的活性. 这些抑制剂向细胞内膜网膜应激信号,并显示出与过度蛋白质AMPylation相关的疾病治疗的希望.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞应激反应的应激反应
背景情况:
- 该FICD (FLCN交互蛋白D) 酶通过修改BiP/GRP78护卫器来调节内 плазма网膜 (ER) 中的压力信号.
- FICD对BiP/GRP78的失调AMPylation与各种人类疾病有关.
- 对致病性FICD变体缺乏特定的小分子抑制剂阻碍了治疗的发展.
研究的目的:
- 识别和验证抑制FICD活动的小分子.
- 探索FICD抑制剂对与异常蛋白AMPylation相关的疾病的治疗潜力.
主要方法:
- 在试验室中使用高通量选试验来识别FICD抑制剂.
- 基于细胞的测试被用来评估已识别的抑制剂对BiP/GRP78AMPylation和deAMPylation的疗效.
- 评估了抑制剂对致病性FICD变体和细胞功能 (亲胰岛素处理) 的影响.
主要成果:
- 确定了两种新的小分子FICD抑制剂,C22和C73.
- 在细胞模型中,C22和C73有效抑制FICD介导的BiP/GRP78AMPylation.
- 这些抑制剂对致病性FICD变体表现出有效性,并改善β细胞功能.
结论:
- 小分子C22和C73代表了针对FICD的有前途的治疗剂.
- 抑制FICD介导的AMPylation为治疗与ER压力相关的疾病提供了一个新的策略.
- 这项研究验证了FICD作为治疗干预的可用药物标.
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