Molecular Recognition of Potassium Channels

描述（由申请人提供）：本研究计划的目标是将联合收割机有机合成与结构生物学的最新进展相结合，为分子识别和神经生物学领域做出重大贡献。 我们建议开发四重对称，合成配体，识别四聚体离子通道，特别是钾离子通道。该研究的主要目标是提供一套大的分子探针，以区分不同类型的钾通道或调节其功能特性。这些化合物可能是神经生物学研究中有用的工具。人们希望这些化合物最终能在钾通道的选择性识别方面超过抗体和肽毒素。最终，拟议的研究可能会导致针对各种疾病的新型治疗药物，如自身免疫性疾病，糖尿病以及精神或心脏疾病。 具体而言，提出了用于电压门控钾通道如KvAP、Shaker和人Kv1.x通道的设计配体的合成和生物学评价。药理学相关的Kv1.x通道，如Kv1.3或Kv1.5将受到特别关注。将评价合成配体结合给定通道的不同功能状态的能力。

DESCRIPTION (provided by applicant): The goal of this research proposal is to combine organic synthesis with recent advances in structural biology to make significant contributions both to the fields of molecular recognition and neurobiology. We propose to develop fourfold symmetrical, synthetic ligands that recognize tetrameric ion channels, in particular potassium channels. The primary goal of the proposed research is to provide a large set of molecular probes that discriminate among different types of potassium channels or modulate their functional properties. These compounds could be useful tools in neurobiological studies. It is hoped that these compounds will eventually surpass antibodies and peptide toxins in the selective recognition of potassium channels. Ultimately, the proposed research might lead to novel therapeutic agents against various ailments such as autoimmune disorders, diabetes as well as mental or cardiac diseases. Specifically, the synthesis and biological evaluation of designed ligands for voltage-gated potassium channels such as KvAP, Shaker, and human Kv1.x channels is proposed. Pharmacologically relevant Kv1.x channels such as Kv1.3 or Kv1.5 will receive special attention. The ability of the synthetic ligands to bind to different functional states of a given channel will be evaluated.