Analogs of the sea anemone potassium channel blocker ShK for the treatment of autoimmune diseases.
Analogs of the sea anemone potassium channel blocker ShK for the treatment of autoimmune diseases.
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海葵钾通道阻滞剂 ShK 的类似物，用于治疗自身免疫性疾病。
DOI：
10.2174/187152811797200641
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Norton RS
中科院分区：
文献类型：
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作者：
Beeton C;Pennington MW;Norton RS
CCR 7-效应记忆T（TEM）淋巴细胞参与自身免疫性疾病，如多发性硬化症，1型糖尿病和类风湿性关节炎。这些细胞表达Kv1.3钾通道，在其激活中起主要作用。阻断这些通道优先抑制CCR 7 − TEM细胞的激活，对CCR 7+幼稚和中央记忆T细胞几乎没有影响。因此，淋巴细胞Kv1.3通道的阻断剂作为自身免疫性疾病的治疗剂显示出相当大的潜力。ShK是从加勒比海海葵Stichodactyla helianthus中分离的35个残基的多肽，在皮摩尔浓度下阻断Kv1.3通道。虽然ShK在治疗迟发型超敏反应和多发性硬化模型大鼠中是有效的，但它对Kv1.3通道缺乏对密切相关的Kv 1通道的选择性。广泛的诱变研究结合ShK结构的阐明导致ShK与通道对接的模型。这些知识在开发具有改进的选择性和增加的稳定性的新ShK类似物中是有价值的，其已被证明在预防和/或治疗迟发型超敏反应、1型糖尿病、类风湿性关节炎和多发性硬化症的动物模型中是有效的，而不诱导全身性免疫抑制。目前正在进一步评估它们作为治疗自身免疫性疾病的潜在免疫调节剂。
CCR7− effector memory T (TEM) lymphocytes are involved in autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis. These cells express Kv1.3 potassium channels that play a major role in their activation. Blocking these channels preferentially inhibits the activation of CCR7− TEM cells, with little or no effects on CCR7+ naïve and central memory T cells. Blockers of lymphocyte Kv1.3 channels therefore show considerable potential as therapeutics for autoimmune diseases. ShK, a 35-residue polypeptide isolated from the Caribbean sea anemone Stichodactyla helianthus, blocks Kv1.3 channels at picomolar concentrations. Although ShK was effective in treating rats with delayed type hypersensitivity and a model of multiple sclerosis, it lacks selectivity for Kv1.3 channels over closely-related Kv1 channels. Extensive mutagenesis studies combined with elucidation of the structure of ShK led to models of ShK docked with the channel. This knowledge was valuable in the development of new ShK analogs with improved selectivity and increasing stability, which have proven efficacious in preventing and/or treating animal models of delayed type hypersensitivity, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis without inducing generalized immunosuppression. They are currently undergoing further evaluation as potential immunomodulators for the treatment of autoimmune diseases.