Salim Heba, Song Jian, Sahni Ashweta, Pei Dehua
Department of Chemistry and Biochemistry , The Ohio State University , 484 West 12th Avenue , Columbus , Ohio 43210 , United States.
School of Pharmacy , Guangdong Pharmaceutical University , Guangzhou , Guangdong Province 510006 , P.R. China.
J Org Chem. 2020 Feb 7;85(3):1416-1424. doi: 10.1021/acs.joc.9b02367. Epub 2019 Oct 28.
Macrocyclic peptides have proven to be highly effective inhibitors of protein-protein interactions but generally lack cell permeability to access intracellular targets. We show herein that macrocyclic peptides may be rendered highly cell-permeable and biologically active by conjugating them with a cyclic cell-penetrating peptide (CPP). A previously reported cyclic peptidyl inhibitor against the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2 (Nrf2) interaction ( = 18 nM) was covalently attached to a cyclic CPP through a flexible linker. The resulting bicyclic peptide retained the Keap1-binding activity, resisted proteolytic degradation, readily entered mammalian cells, and activated the transcriptional activity of Nrf2 at nanomolar to low micromolar concentrations in cell culture. The inhibitor provides a useful tool for investigating the biological function of Keap1-Nrf2 and a potential lead for further development into a novel class of anti-inflammatory and anticancer agents. Our data suggest that other membrane-impermeable cyclic peptides may be similarly rendered cell-permeable by conjugation with a cyclic CPP.
大环肽已被证明是蛋白质-蛋白质相互作用的高效抑制剂，但通常缺乏细胞通透性以作用于细胞内靶点。我们在此表明，通过将大环肽与环状细胞穿透肽（CPP）偶联，可使其具有高度的细胞通透性和生物活性。一种先前报道的针对 Kelch 样 ECH 相关蛋白 1（Keap1）-核因子红细胞 2（Nrf2）相互作用的环状肽基抑制剂（ = 18 nM）通过柔性接头共价连接到环状 CPP 上。所得的双环肽保留了 Keap1 结合活性，抵抗蛋白水解降解，易于进入哺乳动物细胞，并在细胞培养中以纳摩尔至低微摩尔浓度激活 Nrf2 的转录活性。该抑制剂为研究 Keap1-Nrf2 的生物学功能提供了有用的工具，并为进一步开发新型抗炎和抗癌药物提供了潜在的先导化合物。我们的数据表明，其他不能透过细胞膜的环状肽可能通过与环状 CPP 偶联而同样具有细胞通透性。
