Exploring Synthetic Ligands for Potassium Channels

该合作项目的目标是合理设计与钾通道相互作用的小分子，并研究其作用机制。将采用各种生物物理工具，包括电生理学和固态NMR（ssNMR）。将研究电压门控钾通道阻断剂的新结合模式，ssNMR将用于发现和快速表征钾通道的新配体。最后，钾通道将被改造成光敏的，以控制神经元的电特性。将开发一组试剂，由亲电试剂、偶氮苯光开关和孔阻断基团组成，以使野生型Shaker钾通道对光有反应，从而避免引入突变基因的需要。在与具有反式光开关的孔非共价结合后，这些试剂将与位于通道外前庭中的氨基酸残基形成共价键。然后，光开关至顺式将收回孔阻断基团并恢复通道的电导。这些系统将通过ssNMR和电生理学进行研究，这两种方法都可以进行动态研究。有了这个奖项，有机和大分子化学项目支持了加州-伯克利大学化学系的Dirk Trauner教授的研究。该奖项与德国研究共同体（DFG）为汉堡大学的Olaf Pongs教授和哥廷根马克斯普朗克生物物理化学研究所的Marc Baldus博士资助的合作奖相协调。这个合作团队正在设计和研究靶向离子通道的分子，特别是钾通道。通过了解小有机分子与这些通道相互作用的新模式，并通过设计和制备允许可预测的通道特性改变的分子，这项研究有望开发出导致新药开发的长期基础。其他长期影响是开发新的神经网络解剖工具的潜力，也许还有恢复视力的新方法。

The goal of this collaborative project is the rational design of small molecules that interact with potassium channels and the investigation of their mechanism of action. A variety of biophysical tools, including electrophysiology and solid-state NMR (ssNMR) will be employed. A new binding mode for blockers of voltage-gated potassium channels will be studied, and ssNMR will be used for the discovery and rapid characterization of new ligands for potassium channels. Finally, potassium channels will be engineered to become light-sensitive in order to develop control over the electrical properties of neurons. A set of reagents will be developed, consisting of an electrophile, an azobenzene photoswitch and a pore-blocking group, in order to render wild-type Shaker potassium channels responsive to light, thus obviating the need to introduce a mutant gene. After non-covalent binding to the pore with the photoswitch in the trans form, these reagents will form a covalent bond to an amino acid residue situated in the outer vestibule of the channel. Photoswitching to the cis form will then retract the pore-blocking group and restore conductance of the channel. These systems will be investigated by ssNMR and electrophysiology, both of which allow for dynamic studies.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professor Dirk Trauner, of the Department of Chemistry at the University of California - Berkeley. This award coordinates with a collaborative award funded by the Deutsche Forschungsgemeinschaft (DFG) for Professor Olaf Pongs, of the University of Hamburg, and Dr. Marc Baldus, of the Max Planck Institute for Biophysical Chemistry, Goettingen. This collaborative team is designing and studying molecules that target ion channels, in particular potassium channels. Through development of an understanding of new modes of interactions of small organic molecules with these channels and by designing and preparing molecules that allow for predictable alteration of channel properties, this research promises to develop fundamental underpinnings leading in the longer term to the development of new drugs. Other longer-term implications are the potential for development of new tools for the dissection of neural networks and, perhaps, new ways to restore vision.