Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents.
Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents.
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DOI：
10.1016/j.apsb.2015.05.008
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Hu L
中科院分区：
文献类型：
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作者：
Abed DA;Goldstein M;Albanyan H;Jin H;Hu L
Keap1-Nrf2-ARE途径是保护细胞免受氧化应激的重要抗氧化防御机制，Keap1-Nrf2蛋白-蛋白质相互作用(PPI)已成为上调ARE控制的细胞保护性氧化应激反应酶表达的重要药物靶点，用于治疗和预防许多疾病和疾病。然而，大多数已知的NRF2激活剂/Are诱导剂是Keap1-NRF2PPI的间接抑制剂，它们是通过修饰Keap1׳S半胱氨酸残基的巯基而起作用的亲电物种。这些间接抑制剂的亲电性可能会与其他重要细胞蛋白的半胱氨酸残基发生反应，从而引起“非靶标”副作用。最近的努力集中在开发Keap1-Nrf2 PPI的直接抑制剂上。本文综述了最近的研究工作，包括高通量筛选方法的发展，多肽和小分子直接抑制物的发现，以及这些抑制物与靶Keap1 Kelch结构域蛋白结合的生物物理特性。这些非共价的Keap1-Nrf2 PPI直接抑制剂有可能被开发成有效的治疗或预防各种疾病和条件的药物。Keap1-Nrf2-ARE途径是保护细胞免受氧化应激的重要抗氧化防御机制。在许多疾病的治疗和预防药物的开发中，非共价直接抑制Keap1-Nrf2蛋白-蛋白相互作用(PPI)已成为上调ARE控制的细胞保护性氧化应激反应酶表达的重要途径。
The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions. The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress. Non-covalent direct inhibition of the Keap1–Nrf2 protein–protein interaction (PPI) has become an important approach to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions.