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。将使用各种生物物理工具，包括电生理学和固态核磁共振(ss核磁共振)。我们将研究电压门控钾通道阻滞剂的一种新的结合模式，并将使用单核磁共振技术来发现和快速表征新的钾通道配体。最后，钾通道将被改造成对光敏感，以发展对神经元电特性的控制。将开发一套试剂，由电泳剂、偶氮苯光开关和孔洞阻断基团组成，以使野生型Shaker钾通道对光做出响应，从而消除引入突变基因的需要。这些试剂通过反式光开关与孔道非共价结合后，将与位于通道外前庭的氨基酸残基形成共价键。然后，光切换到顺式将收缩孔阻挡基团并恢复通道的电导。这些系统将通过核磁共振和电生理学进行研究，两者都允许进行动态研究。有了这个奖项，有机和高分子化学计划将支持加州大学伯克利分校化学系的德克·特劳纳教授的研究。该奖项与由德国联邦理工学院(DFG)资助的汉堡大学Olaf Pong教授和哥廷根马克斯·普朗克生物物理化学研究所的Marc Baldus博士合作颁发的奖项相协调。这个合作团队正在设计和研究针对离子通道，特别是钾通道的分子。通过对小有机分子与这些通道相互作用的新模式的了解，以及通过设计和制备允许通道性质可预测变化的分子，这项研究有望为新药的长期开发奠定基础。其他更长期的影响包括开发新的神经网络解剖工具的潜力，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.