Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Biochem Pharmacol. 2020 Nov;181:114146. doi: 10.1016/j.bcp.2020.114146. Epub 2020 Jul 10.
The voltage-gated potassium channel K1.3 is a well-established therapeutic target for a range of autoimmune diseases, in addition to being the site of action of many venom-derived peptides. Numerous studies have documented the efficacy of venom peptides that target K1.3, in particular from sea anemones and scorpions, in animal models of autoimmune diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis. Moreover, an analogue of the sea anemone peptide ShK (known as dalazatide) has successfully completed Phase 1 clinical trials in mild-to-moderate plaque psoriasis. In this article we consider other potential therapeutic applications of inhibitors of K1.3, including in inflammatory bowel disease and neuroinflammatory conditions such as Alzheimer's and Parkinson's diseases, as well as fibrotic diseases. We also summarise strategies for facilitating the entry of peptides to the central nervous system, given that this will be a pre-requisite for the treatment of most neuroinflammatory diseases. Venom-derived peptides that have been reported recently to target K1.3 are also described. The increasing number of autoimmune and other conditions in which K1.3 is upregulated and is therefore a potential therapeutic target, combined with the fact that many venom-derived peptides are potent inhibitors of K1.3, suggests that venoms are likely to continue to serve as a rich source of new pharmacological tools and therapeutic leads targeting this channel.
电压门控钾通道 K1.3 是多种自身免疫性疾病的成熟治疗靶点，也是许多毒液衍生肽的作用部位。许多研究已经证明了靶向 K1.3 的毒液肽的功效，特别是来自海葵和蝎子的毒液肽，在类风湿性关节炎、银屑病和多发性硬化症等自身免疫性疾病的动物模型中。此外，海葵肽 ShK 的类似物（称为 dalazatide）已成功完成轻度至中度斑块型银屑病的 1 期临床试验。在本文中，我们考虑了 K1.3 抑制剂的其他潜在治疗应用，包括炎症性肠病和神经炎症性疾病，如阿尔茨海默病和帕金森病，以及纤维化疾病。我们还总结了促进肽进入中枢神经系统的策略，因为这是治疗大多数神经炎症性疾病的前提。最近报道的靶向 K1.3 的毒液衍生肽也进行了描述。越来越多的自身免疫性疾病和其他 K1.3 上调的疾病，因此是潜在的治疗靶点，再加上许多毒液衍生肽是 K1.3 的有效抑制剂，这表明毒液很可能继续成为针对这种通道的新药理学工具和治疗先导的丰富来源。
