Molecular interaction between the voltage-dependent anion channel 2 and its agonist efsevin

心血管疾病在全世界的死亡率和保健费用统计中仍然占主导地位。尽管存在这些令人担忧的事实，但目前治疗心律失常和心力衰竭的方法有限，而且目前大多数药物，如抗心律失常药物和正性肌力药物，都显示出严重的副作用。因此，开发治疗心血管疾病的新治疗策略是我们这个时代的主要临床前工作。我们最近发现了线粒体在调节心脏节律性和收缩性方面的重要作用。新合成的化合物efsevin对线粒体外膜电压依赖性阴离子通道2 （VDAC2）的药理激活增强了线粒体钙摄取，从而限制了斑马鱼心脏和离体小鼠心律失常模型心肌细胞的心律失常事件。然而，efsein - vdac2相互作用的分子性质仍然难以捉摸。本研究旨在从生物化学和生物物理的角度探讨这种相互作用。通过将纯化的VDAC2蛋白整合到平面脂质双层中，我们将研究efsevin结合后通道门控行为的生物物理变化。这将加深我们对药物作用机制的理解，也是探索VDAC2作为药物靶点的关键一步。此外，我们将确定efsevin的结合效率，并确定efsevin在VDAC2通道蛋白上的结合位点。这将为优化化合物的结构导向设计铺平道路。最后，我们将在衍生物筛选中确定更有效的埃夫塞文衍生物，并测试它们的治疗潜力。该项目的成功将是朝着建立治疗心血管疾病的新药理靶点迈出的重要一步。通过选择性地靶向细胞内靶结构，这些药物预计不会影响心脏动作电位，因此与普通实际药物相比，副作用更小。

Cardiovascular diseases still dominate the statistics of mortality and health-care expenses worldwide. Despite these alarming facts current treatment options for arrhythmia and heart failure are limited and most current drugs, like antiarrhythmics and positive inotropic substances, display major side effect. The development of novel therapeutic strategies for the treatment of cardiovascular disease is thus a major pre-clinical endeavor of our time. We have recently identified an important role of mitochondria for regulation of cardiac rhythmicity and contractility. Pharmacological activation of the outer mitochondrial membrane voltage-dependent anion channel 2 (VDAC2) by the newly synthesized compound efsevin enhances mitochondrial calcium uptake and thereby restricts arrhythmogenic events in zebrafish hearts and isolated murine cardiomyocytes of a cardiac arrhythmia model. However the molecular nature of the efsevin-VDAC2 interaction remains elusive. This proposal seeks to investigate this interaction on a biochemical and biophysical level. Using purified VDAC2 protein incorporated into planar lipid bilayers we will investigate biophysical changes in gating behavior of the channel upon efsevin binding. This will deepen our understanding of the mechanism of drug action and will be a crucial step in the exploration of VDAC2 as a drug target. Furthermore, we will determine binding efficiency of efsevin and identify the binding site of efsevin on the VDAC2 channel protein. This will pave the way for structure guided design of optimized compounds. Finally, we will identify more potent derivatives of efsevin in a derivative screen and test those for their therapeutic potential. Success of this project will be an important step towards the establishment of a novel pharmacological target for the treatment of cardiovascular diseases. By selectively targeting intracellular target structures these agents are expected not to influence the cardiac action potential and thus to display less side effects compared to common actual drugs.