Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University, 5 Xinmofan Road, Nanjing, 211816, P. R. China.
The Institute of Flexible Electronics (IFE, Future Technologies), Xiamen University, 422 Siming South Road, Xiamen, 361005, P. R. China.
Chembiochem. 2023 Jul 3;24(13):e202200748. doi: 10.1002/cbic.202200748. Epub 2023 Jun 2.
C-Jun N-terminal kinase (JNK) is a key mediator involved in a variety of physiological processes. JNK activation is regulated in a complex manner by upstream kinases and phosphatases, and plays an important role in physiological processes such as the immune response and neuronal function. Therefore, JNK has become a therapeutic target for neurodegenerative diseases, ankylosing spondylitis, psoriasis, arthritis and other diseases. Inhibition of JNK activation in mitochondria holds great potential for Parkinson's disease (PD) therapy. However, no specific mitochondrial-targeted JNK inhibitor has been reported. We have developed a mitochondrial-targeted JNK inhibitor, P2, by linking a mitochondrial-specific cell-penetrating peptide to SP600125 (SP), a commercialized specific inhibitor of JNK. We found that P2 specifically inhibited mitochondrial JNK phosphorylation instead of nuclear JNK signaling. Further studies showed that P2 effectively rescued PD phenotypes both in vitro and in vivo, thus indicating that it is a potential therapeutic for PD.
C-Jun N-terminal kinase (JNK) 是一种参与多种生理过程的关键介质。JNK 的激活受到上游激酶和磷酸酶的复杂调节，在免疫反应和神经元功能等生理过程中发挥着重要作用。因此，JNK 已成为治疗神经退行性疾病、强直性脊柱炎、银屑病、关节炎等疾病的靶点。抑制线粒体中的 JNK 激活在帕金森病（PD）治疗中具有很大的潜力。然而，目前尚未报道有专门针对线粒体的 JNK 抑制剂。我们通过将线粒体特异性的穿透肽与 JNK 的商业化特异性抑制剂 SP600125（SP）连接，开发了一种线粒体靶向的 JNK 抑制剂 P2。我们发现 P2 特异性抑制了线粒体 JNK 的磷酸化，而不是核 JNK 信号。进一步的研究表明，P2 有效地在体外和体内挽救了 PD 表型，这表明它是一种治疗 PD 的潜在药物。
