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通过抑制Keap1-Nrf2蛋白-蛋白相互作用激活Nrf2

Nrf2 activation through the inhibition of Keap1-Nrf2 protein-protein interaction.

作者信息

Lee Sumi, Hu Longqin

机构信息

Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, United States.

Cancer Institute of New Jersey, New Brunswick, New Jersey 08901, United States.

出版信息

Med Chem Res. 2020 May;29(5):846-867. doi: 10.1007/s00044-020-02539-y. Epub 2020 Apr 10.

DOI:10.1007/s00044-020-02539-y
PMID:32390710
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7207041/
Abstract

Activation of the transcription factor Nrf2 via the Keap1-Nrf2-ARE signaling system regulates the transcription and subsequent expression of cellular cytoprotective proteins and plays a crucial role in preventing pathological conditions exacerbated by the overproduction of oxidative stress. In addition to electrophilic modulators, direct non-covalent inhibitors that interrupt the Keap1-Nrf2 protein-protein interaction (PPI) leading to Nrf2 activation have attracted a great deal of attention as potential preventive and therapeutic agents for oxidative stress-related diseases. Structural studies of Keap1-binding ligands, development of biochemical and cellular assays, and new structure-based design approaches have facilitated the discovery of small molecule PPI inhibitors. This perspective reviews the Keap1-Nrf2-ARE system, its physiological functions, and the recent progress in the discovery and the potential applications of direct inhibitors of Keap1-Nrf2 PPI.

摘要

通过Keap1-Nrf2-ARE信号系统激活转录因子Nrf2可调节细胞保护性蛋白的转录及后续表达，并在预防因氧化应激过度产生而加剧的病理状况中发挥关键作用。除亲电调节剂外，作为氧化应激相关疾病的潜在预防和治疗药物，能够中断Keap1-Nrf2蛋白-蛋白相互作用（PPI）从而导致Nrf2激活的直接非共价抑制剂也引起了广泛关注。Keap1结合配体的结构研究、生化和细胞检测方法的开发以及基于新结构的设计方法促进了小分子PPI抑制剂的发现。本文综述了Keap1-Nrf2-ARE系统、其生理功能以及Keap1-Nrf2 PPI直接抑制剂发现方面的最新进展及其潜在应用。

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