Sodium Channel Contratoxins Derived from Cone Snail Venoms

锥螺毒液中提取的钠通道Contratoxins

• 批准号: 7129569
• 负责人: GRZEGORZ BULAJ
• 金额: $ 20.18万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7129569
• 关键词: analog; conotoxin; ions; neurotoxins; sodium channel; toxin

DESCRIPTION (provided by applicant): Neurotoxins that target ion channels are among the chemicals that NIH has identified as at the nexus of neuroscience research and counterterrorism. Archetypal examples in this regard are the alkaloids tetrodotoxin (TTX) and saxitoxin (SIX), both potent paralytic agents that act by binding to the same site on, and blocking the function of voltage-gated sodium channels. We propose to develop a conceptually novel antagonist of these and related neurotoxins. The concept is encapsulated by the term contratoxin, defined as follows: an agent that binds the target of a toxin and shields the target from the toxin. To provide proof-of-concept contratoxin data, we will utilize conotoxins, peptide-based neurotoxins produced by venomous cone snails. Their exquisite potency and selectivity toward individual ion channels or receptors have been shown in many instances. In this exploratory proposal, our experimental strategy consists of three parallel approaches to obtain contratoxins against TTX/STX: (1) rational design, (2) molecular biology/chemical synthesis and (3) screening natural product libraries. In each aim, candidate contratoxins will be tested for their inability to block sodium channels on one hand and their ability to block the action of TTX/STX on the other. In the Specific Aim I, we will rationally design conotoxin GIIIA-based analogs, followed by a chemical synthesis and functional evaluation. These so-called "leaky" analogs will target the TTX/STX binding site on sodium channels, but void paralytic activity. In addition, we propose to screen for a contratoxin activity among selected conotoxins discovered by molecular cloning or/and from fractionated venom components of invertebrate-hunting cone snails (Specific Aims II and III, respectively). Our long- term goal is to develop contratoxins as novel tools that will be utilized across multiple fields, including neuroscience, neuropharmacology and medical countermeasures against neurotoxic agents. This research is also expected to illuminate the way for investigations of other contratoxins, such as those against TTX/STX on neuronal sodium channels as well as against other neurotoxins with other ion channel targets.

描述（由申请人提供）：靶向离子通道的神经毒素属于NIH已确定为神经科学研究和反恐怖主义的化学物质。这方面的原型例子是生物碱四毒素（TTX）和萨克西毒素（六），它们都是通过与同一位点结合起来的有效的麻痹剂，并阻止了电压门控钠通道的功能。我们建议开发一种概念上新颖的拮抗剂和相关的神经毒素。该概念由术语旋转毒素封装，定义为如下：一种结合毒素靶标并将靶标靶向毒素的代理。为了提供概念验证毒素数据，我们将利用由毒锥蜗牛产生的基于肽的神经毒素的结合毒素。在许多情况下，它们对单个离子通道或受体的精致效力和选择性已经显示出来。在此探索性建议中，我们的实验策略包括三种相关的方法，以获得针对TTX/STX的矛盾素：（1）理性设计，（2）分子生物学/化学合成和（3）筛选天然产物库。在每个目标中，候选对毒素的一方面无法阻止钠通道以及阻止TTX/STX对另一方面的作用的能力进行测试。在特定的目的I中，我们将合理设计基于GIIIA的类似物，然后进行化学合成和功能评估。这些所谓的“泄漏”类似物将针对钠通道上的TTX/STX结合位点，但无效的麻痹活性。此外，我们建议在通过分子克隆或/和/和/和/和/和/和//////和无脊椎动物狩猎锥蜗牛的分离毒液成分中发现的选定结合毒素中的矛盾活性（分别分别为II和III）。我们的长期目标是开发连锁毒素作为新工具，这些工具将在多个领域中使用，包括神经科学，神经药理学和针对神经毒性剂的医学对策。预计这项研究还可以阐明其他对毒素的研究，例如在神经元钠通道上针对TTX/STX的毒素，以及针对其他具有其他离子通道靶标的其他神经毒素。