Abstract：
Potassium ion transport across myocardial cell membrane is essential for type 2 long QT syndrome (LQT2). However, the dysfunction of potassium ion transport due to genetic mutations limits the therapeutic effect in treating LQT2. Biomimetic ion channels that selectively and efficiently transport potassium ions across the cellular membranes are promising for the treatment of LQT2. To corroborate this, we synthesized a series of foldamer-based ion channels with different side chains, and found a biomimetic ion channel of K+ (BICK) with the highest transport activity among them. The selected BICK can restore potassium ion transport and increase transmembrane potassium ion current, thus shortening phase 3 of action potential (AP) repolarization and QT interval in LQT2. Moreover, BICK does not affect heart rate and cardiac rhythm in treating LQT2 model induced by E4031 in isolated heart as well as in guinea pigs. By restoring ion transmembrane transport tactic, biomimetic ion channels, such as BICK, will show great potential in treating diseases related to ion transport blockade. STATEMENT OF SIGNIFICANCE: Type 2 long QT syndrome (LQT2) is a disease caused by K+ transport disorder, which can cause malignant arrhythmia and even death. There is currently no radical cure, so it is critical to explore ways to improve K+ transmembrane transport. In this study, we report that a small-molecule biomimetic ion channel BICK can efficiently simulate natural K+ channel proteins on the cardiomyocyte and cure E4031-induced LQT2 in guinea pig by restoring K+ transport function for the first time. This study found that the potassium transmembrane transport by BICK significantly reduced the QT interval, which provides a conceptually new strategy for the treatment of LQT2 disease.
摘要：
钾离子穿过心肌细胞膜的转运对于2型长QT综合征（LQT2）至关重要。然而,基因突变导致的钾离子转运功能障碍限制了LQT2的治疗效果.选择性和有效地将钾离子转运穿过细胞膜的仿生离子通道有望用于LQT2的治疗。为了证实这一点，我们合成了一系列具有不同侧链的基于foldamer的离子通道，发现了其中转运活性最高的仿生离子通道K+(BICK)。选择的BICK可以恢复钾离子的运输和增加跨膜钾离子电流，从而缩短LQT2中动作电位（AP）复极化和QT间期的3相。此外，BICK在治疗由E4031诱导的LQT2模型中在离体心脏以及豚鼠中不影响心率和心律。通过恢复离子跨膜运输策略，仿生离子通道,比如BICK,在治疗与离子传输阻断相关的疾病方面将显示出巨大的潜力。意义声明：2型长QT综合征（LQT2）是由钾转运障碍引起的疾病，会导致恶性心律失常甚至死亡.目前还没有根治的方法,因此，探索改善K+跨膜转运的方法至关重要。在这项研究中,我们报道，小分子仿生离子通道BICK可以有效地模拟心肌细胞上的天然K通道蛋白，并通过首次恢复K转运功能来治愈E4031诱导的豚鼠LQT2。本研究发现BICK的钾跨膜转运显著缩短了QT间期,这为LQT2疾病的治疗提供了一个概念上的新策略。
