A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.
A cell-active cyclic peptide targeting the Nrf2/Keap1 protein-protein interaction.
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一种靶向Nrf2/Keap1蛋白质 - 蛋白质相互作用的细胞活性环肽
DOI：
10.1039/d3sc04083f
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发表时间：
2023-10-11
期刊：
影响因子：
8.4
通讯作者：
Spring DR
中科院分区：
文献类型：
--
作者：
Iegre J;Krajcovicova S;Gunnarsson A;Wissler L;Käck H;Luchniak A;Tångefjord S;Narjes F;Spring DR
破坏Nrf 2和Keap 1之间的蛋白质-蛋白质相互作用（PPI）是一种有吸引力的策略，可以抵消各种严重疾病的氧化应激。肽代表了用于抑制这种治疗上重要的PPI的小分子的补充方法。然而，由于它们的极性性质和与Keap 1结合所需的负净电荷，迄今报道的肽在细胞中表现出中等微摩尔活性或无活性。在此，我们提出了一种双组分肽钉合策略，以快速获得靶向Nrf 2/Keap 1 PPI的各种受限和功能化肽。最有前途的肽，P8-H含有脂肪酸标签，结合Keap 1与纳摩尔亲和力，并在亚微摩尔浓度的人肺上皮细胞系中诱导ARE基因的转录是有效的。此外，与Keap 1复合的肽的晶体学产生了高分辨率的X射线结构，增加了可用于开发细胞渗透性拟肽抑制剂的结构工具箱。应用DVP钉合方法有效开发Nrf 2肽，其在酶测定中具有nM活性，在细胞中具有亚微摩尔活性且无细胞毒性，其特征在于高分辨率X射线共晶体学。
The disruption of the protein–protein interaction (PPI) between Nrf2 and Keap1 is an attractive strategy to counteract the oxidative stress that characterises a variety of severe diseases. Peptides represent a complementary approach to small molecules for the inhibition of this therapeutically important PPI. However, due to their polar nature and the negative net charge required for binding to Keap1, the peptides reported to date exhibit either mid-micromolar activity or are inactive in cells. Herein, we present a two-component peptide stapling strategy to rapidly access a variety of constrained and functionalised peptides that target the Nrf2/Keap1 PPI. The most promising peptide, P8-H containing a fatty acid tag, binds to Keap1 with nanomolar affinity and is effective at inducing transcription of ARE genes in a human lung epithelial cell line at sub-micromolar concentration. Furthermore, crystallography of the peptide in complex with Keap1 yielded a high resolution X-ray structure, adding to the toolbox of structures available to develop cell-permeable peptidomimetic inhibitors. Application of DVP stapling methodology to efficiently develop Nrf2 peptides with nM activity in enzymatic assays, submicromolar activity in cells and non-cytotoxicity, characterised by high resolution X-ray co-crystallography.
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影响因子：
3.8
作者：
Chen, Ke;Huang, Liuliu;Shen, Bin
通讯作者：
Shen, Bin
影响因子：
4.6
作者：
Lönn P;Kacsinta AD;Cui XS;Hamil AS;Kaulich M;Gogoi K;Dowdy SF
通讯作者：
Dowdy SF
影响因子：
7.3
作者：
Davies, Thomas G.;Wixted, William E.;Kerns, Jeffrey K.
通讯作者：
Kerns, Jeffrey K.
影响因子：
7.4
作者：
Canning P;Sorrell FJ;Bullock AN
通讯作者：
Bullock AN
影响因子：
13.3
作者：
通讯作者：
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