相关实验视频

Updated: Sep 10, 2025

Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA

Author Spotlight: Streamlining Protein Target Prediction and Validation via Molecular Docking and CETSA

Published on: February 23, 2024

基于片段的药物发现新型高亲和性,选择性和抗炎性Keap1-Nrf2蛋白相互作用的抑制剂

Chunyu Lin¹, Dilip Narayanan¹, Marilia Barreca^1,2

¹Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark.

Angewandte Chemie (International ed. in English)

|August 21, 2025

概括

使用基于片段的药物发现方法开发了针对Keap1-Nrf2相互作用的新型非对应抑制剂. 这些化合物具有强烈的抗炎作用,并激活细胞保护性通路,

科学领域:

医学化学
分子药理学
药物发现

背景情况:

激活核红素因子2相关因子2 (Nrf2) 途径可以提供对氧化应激和炎症的细胞保护作用.
抑制凯尔赫类ECH相关蛋白1 (Keap1) 和Nrf2之间的相互作用是关键策略,非共价抑制剂可能比共价替代品具有更高的特异性.
由于其大小和极性,Keap1 Kelch结合口袋对开发类似药物的非共价抑制剂提出了挑战.

研究的目的:

开发针对Keap1-Nrf2蛋白与蛋白相互作用的新型非共价抑制剂.
为优化Keap1Kelch域的抑制器亲和力和选择性.
评估已开发的抑制剂的细胞活性和抗炎作用.

主要方法:

基于碎片的药物发现是从一个结晶学识别的弱点开始的.
使用X射线共晶结构和两步复合生长策略的结构引导优化.
细胞测试以评估Nrf2控制的基因表达,炎症和STING信号,以及用于途径分析的RNA测序.

主要成果:

合成了一系列具有低纳米分子亲和度的非共价Keap1-Nrf2抑制剂.
化合物在同类凯尔奇域组中对Keap1具有很高的选择性.
选择的化合物 (24和28) 强烈激活了Nrf2依赖的基因表达,并通过降低NLRP3炎症和STING信号来表现出抗炎作用.
RNA测序显示了与共价Nrf2激活剂不同的细胞保护通路的激活.

结论:

基于片段的药物发现是针对Keap1-Nrf2等具有挑战性的蛋白质相互作用的可行方法.
新型非共价Keap1-Nrf2抑制剂为生物研究提供了有前途的化学探针.
这些化合物作为开发针对氧化应激和炎症疾病的治疗方法的有价值的药物.

关键词:

基于碎片的药物发现炎症发生凯普1 氧化应激蛋白与蛋白的相互作用

更多相关视频

Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling

Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling

Published on: July 26, 2017

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

相关概念视频

NF-κB-dependent Signaling Pathway

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...

Protein-protein Interfaces

Protein-protein Interfaces

Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...