声波刺/补丁相互作用的宏环抑制剂的设计和演变
Andrew E Owens1, Ivan de Paola1, William A Hansen2
1Department of Chemistry, University of Rochester , 120 Trustee Road, Rochester, New York 14627, United States.
Journal of the American Chemical Society
|August 1, 2017
概括
研究人员开发了一种新型的宏环抑制剂 (HL2-m5),其向的是声波刺/补丁相互作用. 这种强有力的抑制剂有效地阻断了刺信号和Gli控制的基因转录,为癌症研究提供了新的工具.
科学领域:
- 分子生物学
- 生物化学
- 药物发现
背景情况:
- 刺 (Hh) 信号通路在胚胎发育中至关重要,并与各种癌症有关.
- 现有的Hh通路调节器主要针对平滑的受体,使得上游相互作用的探索较少.
- 一个关键的上游事件 - - 声波刺 (Shh) /补丁相互作用的强有力的抑制剂是很难开发的.
研究的目的:
- 开发出强大的SHH/补丁相互作用抑制剂.
- 创建一个新的宏环调节器的Hh路径.
- 为研究在疾病中依赖联体的Hh通路激活提供一种工具.
主要方法:
- 基于HHIP Shh结合环的基因编码循环的设计.
- 在大肠杆菌中生成的库中使用宏环的 afinity 成熟.
- 在细胞测试中对结亲和度 (KD) 和抑制活性 (IC50) 的表征.
主要成果:
- 一种优化的宏环抑制剂HL2-m5被开发出来,Shh的KD为170nM,代表了120倍的亲和力改善.
- 在细胞中,HL2- m5有效抑制了Shh介导的Hh信号和Gli控制的基因转录 (IC50=230nM).
- 这是迄今为止报告的Shh/ 补丁相互作用最强的抑制剂.
结论:
- 成功开发了Shh/补丁相互作用的第一类宏环抑制剂 (HL2- m5).
- 这种抑制剂作为一种有价值的探针,用于在癌症和其他病理中调查和向依赖Hh通路的激活.
- 这项研究引入了一种可通用的策略,用于开发蛋白质与蛋白质相互作用的环抑制剂.
更多相关视频
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
11.9K
08:10Using Confocal Analysis of Xenopus laevis to Investigate Modulators of Wnt and Shh Morphogen Gradients
Published on: December 14, 2015
11.9K
相关概念视频
02:33Hedgehog Signaling Pathway
10.2K
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
10.2K
03:14Notch Signaling Pathway
6.7K
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
6.7K
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
2.5K
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
2.5K