We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated K_V1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to K_V1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for K_V1.3 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 ¹⁸F-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 in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.

中文翻译：

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膜穿透，联合靶向免疫调节植物防御素对淋巴细胞钾通道KV1.3的调节。

我们描述了一个富含半胱氨酸，膜穿透，联合靶向和非常稳定的肽EgK5，通过独特的机制调节T淋巴细胞中电压门控的K _V 1.3钾通道。EgK5进入质膜并与K _V 1.3结合，通过磷脂酰肌醇4,5-双磷酸酯依赖性机制导致电流减少。EgK5对K _V 1.3的选择性超过其他通道，受体，转运蛋白和酶。EgK5抑制了抗原触发的效应记忆T细胞的增殖，效应记忆T细胞是自身免疫性疾病中致病性自身反应性T细胞中富集的子集。PET-CT成像¹⁸F标记的EgK5显示出肽在啮齿动物的大大小小的关节中的积累。EgK5与它的关节运动保持一致，可以治疗类风湿关节炎大鼠模型中的疾病。它还在特应性皮炎大鼠模型中有效治疗疾病。在体内剂量的10–100倍时未观察到毒性迹象。EgK5有望作为一种临床治疗自身免疫性疾病的药物。