Ong Seow Theng, Bajaj Saumya, Tanner Mark R, Chang Shih Chieh, Krishnarjuna Bankala, Ng Xuan Rui, Morales Rodrigo A V, Chen Ming Wei, Luo Dahai, Patel Dharmeshkumar, Yasmin Sabina, Ng Jeremy Jun Heng, Zhuang Zhong, Nguyen Hai M, El Sahili Abbas, Lescar Julien, Patil Rahul, Charman Susan A, Robins Edward G, Goggi Julian L, Tan Peng Wen, Sadasivam Pragalath, Ramasamy Boominathan, Hartimath Siddana V, Dhawan Vikas, Bednenko Janna, Colussi Paul, Wulff Heike, Pennington Michael W, Kuyucak Serdar, Norton Raymond S, Beeton Christine, Chandy K George
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Experimental Medicine Building, 59 Nanyang Drive, Singapore 636921.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, United States.
ACS Pharmacol Transl Sci. 2020 May 14;3(4):720-736. doi: 10.1021/acsptsci.0c00035. eCollection 2020 Aug 14.
We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for K1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10-100 times the dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.
我们描述了一种富含半胱氨酸、具有膜穿透性、靶向关节且稳定性极高的肽，即EgK5，它通过一种独特的机制调节T淋巴细胞中的电压门控K1.3钾通道。EgK5进入质膜并与K1.3结合，通过一种磷脂酰肌醇4,5 - 二磷酸依赖性机制导致电流衰减。与其他通道、受体、转运蛋白和酶相比，EgK5对K1.3具有选择性。EgK5抑制效应记忆T细胞的抗原触发增殖，效应记忆T细胞是自身免疫疾病中致病性自身反应性T细胞中富集的一个亚群。用F标记的EgK5进行PET - CT成像显示该肽在啮齿动物的大小关节中积累。与它的关节嗜性一致，EgK5在类风湿性关节炎大鼠模型中可治疗疾病。它在特应性皮炎大鼠模型中治疗疾病也有效。在剂量为10至100倍时未观察到毒性迹象。EgK5作为一种自身免疫疾病治疗药物显示出临床开发的前景。
