钾离子通道Kv1.5由于特殊的组织电生理特征，作为房颤治疗的理想靶标受到广泛关注。寻找靶点专一、机制明确的Kv1.5选择性抑制剂是该类药物的研究重点。近期本课题组在研究海洋蓝藻毒素Aplysiatoxins中发现了一系列具有选择性抑制Kv1.5通道电流的衍生物，且活性化合物对磷酸化PKC激酶表现出两类不同的构效关系。进而推测衍生物可能通过两种机制调控Kv1.5通道电流：直接阻滞机制和PKC介导的磷酸化调控机制。基于以上发现，本项目拟采用天然产物化学、分子药理学和离子通道电生理技术，并结合计算机模拟手段，1）探究Aplysiatoxin衍生物的结构多样性与Kv1.5抑制作用相关性，挖掘具有强选择性的先导化合物； 2）a. 确证Kv1.5离子通道的直接阻滞位点，及其选择性抑制的分子基础；b. 探究PKC激酶介导的Kv1.5离子通道磷酸化调控机制。为开发房颤治疗的创新型先导化合物提供思路和方向。

Kv1.5, a potassium ion channel, has drawn much attention as an ideal target for atrial fibrillation treatment due to its special electrophysiological characteristics. The search for Kv1.5 selective inhibitors with specific target and clear mechanism is the research focus of developing these drugs. Recently, in the study of marine cyanotoxins Aplysiatoxins, our research group has discovered a series of derivatives with selective inhibition of Kv1.5 channel current, and the active compounds showed two different structure-activity relationships for phosphorylation of PKC kinase. Therefore, it is speculated that the derivatives may regulate Kv1.5 channel current through two mechanisms: direct blocking mechanism and PKC-mediated phosphorylation regulation mechanism. Based on the above findings, we intend to use natural product chemistry, molecular pharmacology and ion channel electrophysiological techniques, combined with computer simulation, 1) To explore the correlation between the structural diversity of Aplysiatoxin derivatives and Kv1.5 inhibition, resulting in the discovery of the lead compounds with strong selectivity; 2) a. To identify the sites of direct blockade of the Kv1.5 ion channel and its molecular basis for selective inhibition by Aplysiatoxins; b. To study the mechanism of PKC kinase-mediated phosphorylation of Kv1.5 ion channel regulated by Aplysiatoxins. Provide guidelines and directions for the development of innovative lead compounds for the treatment of atrial fibrillation.