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小分子FICD抑制剂抑制内源性和病理性的FICD介导蛋白质AMPylation
Bhaskar K Chatterjee1, Maroof Alam2, Arghya Chakravorty3
1Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS chemical biology
|March 4, 2025
概括
研究人员确定了两种小分子,C22和C73,它们抑制FICD,FICD是一种与内质网膜压力和人类疾病相关的酶. 这些抑制剂在治疗与过度蛋白质AMPylation相关的疾病方面表现有前途.
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:
- 酶FICD (胆转移酶) 通过修改BiP/GRP78的陪伴剂来调节内质网膜 (ER) 的压力.
- 失调的BiP/GRP78AMPylation与各种人类疾病有关,但没有特定的抑制剂.
- FICD的双功能活动,催化AMP的添加和去除,提出了一个复杂的治疗挑战.
研究的目的:
- 识别和验证抑制FICD病原性活动的小分子.
- 在疾病的细胞模型中探索FICD抑制剂的治疗潜力.
主要方法:
- 小分子对FICD活动的高通量选.
- 基于细胞的测定以评估BiP/GRP78 AMPylation和deAMPylation的抑制.
- 对致病性FICD变体和β细胞模型中的抑制剂疗效的评估.
主要成果:
- 确定了两种新的小分子抑制剂,C22和C73.
- C22和C73在细胞中有效抑制FICD介导的BiP/GRP78AMPylation,对deAMPylation的影响最小.
- 抑制剂证明了对致病性FICD变异的有效性,并改善了β细胞中的亲胰岛素处理.
结论:
- FICD抑制剂C22和C73代表了一个有前途的新疗法策略.
- 通过FICD抑制向致病性蛋白质AMPylation为治疗相关人类疾病提供了一种新的方法.
- 这些发现为开发抗ER压力相关病理的药物开辟了新的途径.
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