Direct inhibition of Keap1-Nrf2 interaction by egg-derived peptides DKK and DDW revealed by molecular docking and fluorescence polarization
Direct inhibition of Keap1-Nrf2 interaction by egg-derived peptides DKK and DDW revealed by molecular docking and fluorescence polarization
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DOI：
10.1039/c7ra04352j
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发表时间：
2017-01-01
期刊：
影响因子：
3.9
通讯作者：
Zhang, Ting
中科院分区：
文献类型：
--
作者：
Li, Liangyu;Liu, Jingbo;Zhang, Ting
蛋源小肽具有多种生物活性，包括抗氧化活性。Keap 1-Nrf 2通路是细胞抗氧化应激的核心。在这项研究中，我们筛选了一个鸡蛋衍生的短肽库，以确定有可能直接抑制Keap 1-Nrf 2相互作用的分子，使用分子对接，荧光偏振分析，和细胞毒性模型。在分子对接筛选出的20个小肽中，DKK和DDW两个三肽可以直接抑制Keap 1 Kelch结构域与FITC标记的9-mer Nrf 2肽的结合，荧光偏振实验中K-d增加。此外，在H2 O2处理的细胞，DKK和DDW促进生存和上调过氧化氢酶和超氧化物歧化酶的活性，参与解毒的活性氧的关键酶。我们的研究结果表明，小蛋源肽DKK和DDW可以发挥抗氧化作用，并通过直接抑制Keap 1-Nrf 2相互作用保护细胞免受氧化应激。
Egg-derived small peptides have various biological activities, including antioxidant properties. The Keap1-Nrf2 pathway is central to cell resistance to oxidative stress. In this study, we screened an egg-derived short peptide library to identify molecules with a potential to directly inhibit the Keap1-Nrf2 interaction, using molecular docking, fluorescence polarization assay, and a cytotoxicity model. Among the 20 small peptides selected by molecular docking, two tri-peptides, DKK and DDW, could directly inhibit the binding of the Keap1 Kelch domain to the FITC-labelled 9-mer Nrf2 peptide, as evidenced by increased K-d in fluorescence polarization experiments. Furthermore, in H2O2-treated cells, DKK and DDW promoted survival and upregulated the activity of catalase and superoxide dismutase, key enzymes involved in detoxification of reactive oxygen species. Our findings indicate that small egg-derived peptides DKK and DDW can exert antioxidant effects and protect cells against oxidative stress by directly inhibiting Keap1-Nrf2 interaction.