The K_V1.3 voltage-gated potassium ion channel is involved in many physiological processes both at the plasma membrane and in the mitochondria, chiefly in the immune and nervous systems. Therapeutic targeting K_V1.3 with specific peptides and small molecule inhibitors shows great potential for treating cancers and autoimmune diseases, such as multiple sclerosis, type I diabetes mellitus, psoriasis, contact dermatitis, rheumatoid arthritis, and myasthenia gravis. However, no K_V1.3-targeted compounds have been approved for therapeutic use to date. This review focuses on the presentation of approaches for discovering new K_V1.3 peptide and small-molecule inhibitors, and strategies to improve the selectivity of active compounds toward K_V1.3. Selectivity of dalatazide (ShK-186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases. Other peptides and small-molecule inhibitors are critically evaluated for their lead-like characteristics and potential for progression into clinical development. Some small-molecule inhibitors with well-defined structure–activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K_V1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K_V1.3 modulators against this target in the future.

中文翻译：

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KV1.3离子通道抑制剂的发现：药物化学方法和挑战


K _V 1.3 电压门控钾离子通道参与质膜和线粒体的许多生理过程，主要是免疫和神经系统。使用特定肽和小分子抑制剂靶向 K _V 1.3 的治疗显示出治疗癌症和自身免疫性疾病的巨大潜力，例如多发性硬化症、I 型糖尿病、牛皮癣、接触性皮炎、类风湿性关节炎和重症肌无力。然而，迄今为止，尚未批准 K _V 1.3 靶向化合物用于治疗用途。本综述重点介绍发现新 K _V 1.3 肽和小分子抑制剂的方法，以及提高活性化合物对 K _V 1.3 选择性的策略。达拉他嗪 (ShK-186) 是海葵毒素 ShK 的合成衍生物，通过化学修饰实现选择性，并已成功进入临床试验，作为治疗自身免疫性疾病的潜在疗法。其他肽和小分子抑制剂的先导特征和进入临床开发的潜力受到严格评估。一些具有明确结构-活性关系的小分子抑制剂已被优化用于选择性递送至线粒体，并且这些抑制剂为癌症的治疗提供了治疗潜力。 K _V 1.3 抑制剂和方法学的概述旨在为药物发现提供良好的起点，以识别未来针对该靶点的新型有效 K _V 1.3 调节剂。