University of Leuven (KUL), Toxicology and Pharmacology, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, PO Box 922, 3000 Leuven, Belgium.
University of Belgrade, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Vojvode Stepe 450, 11221 Belgrade, Serbia.
Bioorg Chem. 2020 May;98:103746. doi: 10.1016/j.bioorg.2020.103746. Epub 2020 Mar 18.
The voltage-gated potassium channel K1.3 is involved in multiple autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus type 1 and psoriasis. In many auto-immune diseases better treatment options are desired as existing therapies are often ineffective or become less effective over time, for which K1.3 inhibitors arise as promising candidates. In this study, five compounds were selected based on a 3D similarity searching methodology and subsequently screened ex vivo on the K1.3 channel. The screening resulted in two compounds inhibiting the K1.3 channel, of which TVS-12 was the most potent compound, while TVS-06 -although less potent- showed an excellent selectivity for K1.3. For both compounds the mechanism of action was investigated by an electrophysiological characterization on the K1.3 channel and three K1.3 mutants, designed to resemble the pore region of K1.2 channels. Structurally, the presence of a benzene ring and/or an oxane ring seems to cause a better interaction with the K1.3 channel, resulting in a 20-fold higher potency for TVS-12.
电压门控钾通道 K1.3 参与多种自身免疫性疾病，如多发性硬化症、类风湿性关节炎、1 型糖尿病和银屑病。在许多自身免疫性疾病中，人们希望有更好的治疗选择，因为现有的治疗方法往往无效或随着时间的推移效果降低，而 K1.3 抑制剂作为有前途的候选药物出现。在这项研究中，基于 3D 相似性搜索方法选择了五种化合物，并随后在 K1.3 通道上进行了离体筛选。筛选结果显示两种化合物抑制 K1.3 通道，其中 TVS-12 是最有效的化合物，而 TVS-06 -尽管效力较低-对 K1.3 显示出优异的选择性。对于这两种化合物，通过在 K1.3 通道和三个设计为类似于 K1.2 通道孔区的 K1.3 突变体上进行电生理特性研究，研究了其作用机制。从结构上看，苯环和/或氧杂环丁烷的存在似乎与 K1.3 通道有更好的相互作用，导致 TVS-12 的效力提高了 20 倍。
