对NEMO-IκB激酶相互作用的细胞透双循环抑制剂 直接来自组合图书馆
Curran A Rhodes1, Patrick G Dougherty1, Jahan K Cooper1
1Department of Chemistry and Biochemistry , The Ohio State University , 100 West 18th Avenue , Columbus , Ohio 43210 , United States.
研究人员开发了细胞通透的双循环,以向细胞内蛋白质. 这些成功抑制了NEMO- IKKβ相互作用,显示出抗炎和抗癌药物的潜力.
科学领域:
- 医学化学
- 分子生物学
- 药物发现
背景情况:
- 宏环对蛋白具有很高的亲和力和特异性,但通常缺乏细胞透性.
- 通过常规的疗法,仍然难以接触到细胞内目标,例如那些参与信号通路的目标.
- NF-κB信号通路在炎症和癌症中至关重要,使其组件,如NEMO,成为有吸引力的治疗点.
研究的目的:
- 设计和合成能够抑制细胞内蛋白-蛋白相互作用的细胞透性双环.
- 针对NEMO-IKKβ相互作用,对双环的组合库进行选.
- 开发新的治疗方法治疗炎症疾病和癌症.
主要方法:
- 设计和合成具有随机序列和细胞透基因的细胞透性的组合库.
- 对NF-κB基本调节器 (NEMO) 的IκB激酶α/β (IKKα/β) 结合域进行选.
- 生物化学测试以确定抑制度 (IC50) 和基于细胞的测试以评估信号抑制和抗增殖作用.
主要成果:
- 发现了几种细胞通透的双环,抑制了低μM IC50值的NEMO-IKKβ相互作用.
- 优化产生了一种强大的NEMO抑制剂,IC50为1. 0μM.
- 优化的抑制剂选择性地抑制了哺乳动物细胞的NF- kB信号传递,并降低了对西斯普拉丁耐药的卵巢癌细胞增殖.
结论:
- 可以有效地设计细胞透的双环以向细胞内蛋白质相互作用.
- 开发的NEMO抑制剂是研究NEMO/NF-κB生物学的一个有价值的工具.
- 这种抑制剂代表了开发新的抗炎和抗癌疗法的前沿.
更多相关视频
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
07:18A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
相关概念视频
Combinatorial Gene Control
The expression of more than 30,000 genes is controlled by approximately 2000-3000 transcription factors. This is possible because a single transcription factor can recognize more than one regulatory sequence. The specificity in gene...
Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
Protein Kinases and Phosphatases
Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
Permeability of Concrete
