Molecular Recognition of Potassium Channels

描述(申请人提供)：这项研究计划的目标是将有机合成与结构生物学的最新进展结合起来，为分子识别和神经生物学领域做出重大贡献。 我们建议开发四个对称的合成配体来识别四聚体离子通道，特别是钾通道。这项拟议研究的主要目标是提供一大套分子探针，区分不同类型的钾通道或调节其功能特性。这些化合物在神经生物学研究中可能是有用的工具。人们希望这些化合物在选择性识别钾通道方面最终会超过抗体和多肽毒素。最终，这项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。 具体地说，提出了为电压门控钾通道设计的配体的合成和生物学评价，如KvAP、Shaker和人Kv1.x通道。药理上相关的Kv1.x通道，如Kv1.3或Kv1.5，将受到特别关注。将评估合成配体与给定通道的不同功能状态结合的能力。

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.