Exploring Synthetic Ligands for Potassium Channels

这个合作项目的目标是合理设计与钾通道相互作用的小分子，并研究它们的作用机制。各种生物物理工具，包括电生理学和固态核磁共振（ssNMR）将被采用。将研究电压门控钾通道阻滞剂的新结合模式，并将ssNMR用于钾通道新配体的发现和快速表征。最后，钾通道将被设计成光敏的，以控制神经元的电学特性。将开发一套试剂，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钾通道对光有响应，从而避免引入突变基因的需要。这些试剂在与光开关在反式中与孔非共价键结合后，将与位于通道外前庭的氨基酸残基形成共价键。光导转换成顺式形式将收缩孔阻塞基团并恢复通道的电导。这些系统将通过ssmr和电生理学进行研究，这两种方法都允许进行动态研究。通过这个奖项，有机和大分子化学项目支持了加州大学伯克利分校化学系Dirk Trauner教授的研究。该奖项与德国科学研究协会（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以离子通道为目标的分子，特别是钾通道。通过对小有机分子与这些通道相互作用的新模式的理解，以及通过设计和制备允许通道特性可预测改变的分子，本研究有望为新药的长期开发奠定基础。其他更长期的影响是，有可能开发出解剖神经网络的新工具，或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.