Receptor Sites and Antagonists for Paralytic Neurotoxins

麻痹神经毒素的受体位点和拮抗剂

基本信息

批准号：
7470626
负责人：
WILLIAM A CATTERALL
金额：
$ 59.76万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7470626
关键词：
Action Potentials Active Sites Affinity Agonist Alkaloids Amino Acids Bacteria Batrachotoxins Binding Biological Assay Budgets Cells Cessation of life Ciguatoxins Complex Development Dinophyceae Genes Hormones Human In Vitro Infection Laboratories Lead Light Maps Measurement Methods Modeling Molecular Molecular Conformation Movement Muscle Mutagenesis Mutation Nerve Neurotoxins Neurotransmitter Receptor Paralysed Peptides Physiological Poison Research Research Personnel Resolution Rest Role Saxitoxin Scanning Scorpions Shellfish Site Source Structure Surface Terrorism Testing Tetrodotoxin Therapeutic Agents Toxic Actions Toxic effect Toxin Universities Veratridine Virus Work base brevetoxin channel blockers chronic pain concept design drug development in vivo insect paralytic peptide insight molecular modeling mutant nervous system disorder neurotoxin receptor novel novel strategies novel therapeutics polypeptide prevent programs receptor receptor binding scorpion toxin receptor small molecule three-dimensional modeling voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Voltage-gated Na channels are responsible for initiation and propagation of the action potential in vertebrate nerve and muscle. Because of its essential physiological role in movement, the Na channel is a prime target of paralytic neurotoxins, which act at five or more distinct neurotoxin receptor sites. The genes encoding the polypeptide scorpion toxins have been cloned and successfully expressed in bacteria to produce large amounts of these toxins. Therefore, these toxins constitute a substantial terrorist threat as peptides. Moreover, bacteria or viruses expressing the potent polypeptide scorpion toxins are themselves terrorist threats because infection of human hosts with these agents would result in paralysis. The central hypothesis of the work proposed here is that toxin antagonists can be produced that will protect broadly and effectively against paralytic peptide neurotoxins. This hypothesis is supported by a proof-of-concept from our current research, in which the first antagonist of scorpion toxin action has been produced. In the research proposed here, we will define the receptor sites and mechanisms of action of the a- and ¿-scorpion toxins on Na channels, and we will develop therapeutic agents to prevent their toxic actions as well as the toxic actions of mechanistically related peptide neurotoxins from other sources. Our Specific Aims are: 1. Molecular mapping of the scorpion toxin receptor sites on Na channels. 2. Molecular mapping of the active sites of a- and ¿-scorpion toxins. 3. Three-dimensional models of the scorpion toxin receptor sites. 4. Development of novel and potent toxin and small peptide antagonists. All of our work in Specific Aims 1 through 3 immediately flow into the design and development of toxin antagonists in Specific Aim 4 and will significantly advance the effort to develop novel therapeutic agents to protect against the threat of paralytic neurotoxins. These studies will provide new insights into the molecular mechanisms of toxin action on Na channels and will lead to development of effective antagonists of toxin action. These advances will be of crucial importance to developing an arsenal of counter-terrorism agents to prevent illness and deaths from potential bioterrorist attacks using these potent paralytic neurotoxins. In addition to these important advances for counter-terrorism, these studies will shed new light on the molecular mechanisms of voltage sensing and activation gating of Na channels, an essential step toward understanding the molecular mechanisms of electrical excitability and potentially a novel approach to development of drugs to treat chronic pain and neurological disease.

描述（由适用提供）：电压门控的NA通道负责脊椎动物神经和肌肉中动作电位的启动和传播。由于其在运动中具有重要的生理作用，因此NA通道是麻痹神经毒素的主要靶标，其作用于五个或更多不同的神经毒素受体部位。编码多肽蝎毒素的基因已被克隆并在细菌中成功表达，以产生大量这些毒素。因此，这些毒素构成了刺激的恐怖威胁。此外，表达潜在多肽蝎子毒素的细菌或病毒本身就是恐怖威胁，因为用这些药物的人类宿主感染会导致瘫痪。这里提出的工作的中心假设是，可以产生毒素拮抗剂，以广泛有效地保护麻痹性肽神经毒素。这一假设得到了我们当前研究的概念概念的支持，我们目前的研究已经产生了蝎子毒素作用的第一个拮抗剂。在此处提出的研究中，我们将定义接收器位点和A -Scorpion毒素在NA通道上的作用机制，我们将开发治疗剂以防止其有毒作用以及来自其他来源的机械相关肽神经毒素的有毒作用。我们的具体目的是：1。蝎子毒素受体位点在Na通道上的分子映射。 2。A-和®Scorpion毒素的活性位点的分子映射。 3。蝎子毒素受体位点的三维模型。 4。新颖和潜在的毒素和小胡椒拮抗剂的发展。我们在特定目标1到3中的所有工作都立即流入了特定目标4中毒素拮抗剂的设计和开发，并将大大促进开发新型治疗剂以防止瘫痪神经毒素的威胁。这些研究将为NA通道上毒素作用的分子机制提供新的见解，并导致有效的毒素作用拮抗剂的发展。这些进步对于使用这些潜在的麻痹神经毒素的潜在生物恐怖袭击而导致疾病和死亡的反恐药物的武器库至关重要。除了这些重要的反恐进步外，这些研究还将阐明Na通道的电压传感和激活门的分子机制，这是理解电气令人兴奋的分子机制的重要步骤，并有潜在的新方法来开发药物以治疗慢性疼痛和神经系统疾病。