天然产物作为 KEAP1/NRF2 通路的非共价和共价调节剂,发挥抗氧化作用。
Natural products as non-covalent and covalent modulators of the KEAP1/NRF2 pathway exerting antioxidant effects.
机构信息
Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università Degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy.
Department of Cardiovascular, Endocrine-metabolic Diseases, and Aging, Italian National Institute of Health, 00161, Rome, Italy.
出版信息
Eur J Med Chem. 2024 Apr 15;270:116355. doi: 10.1016/j.ejmech.2024.116355. Epub 2024 Mar 26.
By controlling several antioxidant and detoxifying genes at the transcriptional level, including NAD(P)H quinone oxidoreductase 1 (NQO1), multidrug resistance-associated proteins (MRPs), UDP-glucuronosyltransferase (UGT), glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, glutathione S-transferase (GST), sulfiredoxin1 (SRXN1), and heme-oxygenase-1 (HMOX1), the KEAP1/NRF2 pathway plays a crucial role in the oxidative stress response. Accordingly, the discovery of modulators of this pathway, activating cellular signaling through NRF2, and targeting the antioxidant response element (ARE) genes is pivotal for the development of effective antioxidant agents. In this context, natural products could represent promising drug candidates for supplementation to provide antioxidant capacity to human cells. In recent decades, by coupling in silico and experimental methods, several natural products have been characterized to exert antioxidant effects by targeting the KEAP1/NRF2 pathway. In this review article, we analyze several natural products that were investigated experimentally and in silico for their ability to modulate KEAP1/NRF2 by non-covalent and covalent mechanisms. These latter represent the two main sections of this article. For each class of inhibitors, we reviewed their antioxidant effects and potential therapeutic applications, and where possible, we analyzed the structure-activity relationship (SAR). Moreover, the main computational techniques used for the most promising identified compounds are detailed in this survey, providing an updated view on the development of natural products as antioxidant agents.
通过转录水平控制几种抗氧化和解毒基因,包括 NAD(P)H 醌氧化还原酶 1(NQO1)、多药耐药相关蛋白(MRPs)、UDP-葡萄糖醛酸转移酶(UGT)、谷胱甘肽 S-转移酶(GST)、硫氧还蛋白 1(SRXN1)和血红素加氧酶-1(HMOX1),KEAP1/NRF2 通路在氧化应激反应中起着至关重要的作用。因此,发现该通路的调节剂,通过 NRF2 激活细胞信号转导,并针对抗氧化反应元件(ARE)基因,对于开发有效的抗氧化剂至关重要。在这种情况下,天然产物可能代表有前途的候选药物,可用于为人类细胞提供抗氧化能力。在过去的几十年中,通过将计算和实验方法相结合,已经有几种天然产物被表征为通过靶向 KEAP1/NRF2 通路发挥抗氧化作用。在这篇综述文章中,我们分析了几种天然产物,它们通过非共价和共价机制被实验和计算方法研究来调节 KEAP1/NRF2。后一种机制是本文的两个主要部分。对于每一类抑制剂,我们都综述了它们的抗氧化作用和潜在的治疗应用,并在可能的情况下,分析了结构-活性关系(SAR)。此外,本文还详细介绍了针对最有前途的鉴定化合物所使用的主要计算技术,为天然产物作为抗氧化剂的开发提供了最新的观点。