Small Molecule Therapeutics for Botullinum Neurotoxin A

A 型肉毒杆菌神经毒素的小分子疗法

• 批准号: 8052806
• 负责人: TOBIN J DICKERSON
• 金额: $ 115.73万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052806
• 关键词: Acetylcholine; Adsorption; Ames Assay; Animal Model; Animals; Behavior; Binding; Biological Assay; Biology; Bioterrorism; Bontoxilysin; Botulism; Cells; Centers for Disease Control and Prevention (U.S.); Clinical Trials; Collection; Complex; Computer Simulation; Custom; Data; Development; Disease; Dose; Drug Exposure; Drug Kinetics; Ethics; Evaluation; Exhibits; Exocytosis; Exotoxins; Exposure to; Extravasation; Fluorescence Resonance Energy Transfer; Food; Functional disorder; Goals; Grant; Hour; Housing; Human; In Vitro; Instruction; Intervention; Intoxication; Knowledge; Laboratories; Lead; Libraries; Metabolic; Metabolism; Methods; Modeling; Mus; Muscle Weakness; Nerve; Neurotoxins; Oral Administration; Organism; Paralysed; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Phase; Plasma Proteins; Poisoning; Principal Investigator; Production; Property; Protein Binding; Public Health; Recovery; Relative (related person); Reliance; Research; Research Institute; Roentgen Rays; Route; S-nitro-N-acetylpenicillamine; SNAP receptor; Screening procedure; Series; Serotyping; Small Molecule Chemical Library; Solubility; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; Toxin; United States Food and Drug Administration; Universities; Wisconsin; Work; Zinc; absorption; aqueous; base; botulinum; chemical synthesis; combat; cytotoxicity; design; drug development; drug discovery; genotoxicity; high risk; high throughput screening; in vivo; inhibitor/antagonist; lipophilicity; mouse model; nervous system disorder; neuromuscular function; neurotoxicity; neurotransmitter release; pre-clinical; professor; programs; protein protein interaction; repaired; response; small molecule; small molecule libraries; subcutaneous; tool

DESCRIPTION (provided by applicant): Botulism is a neurological disorder caused by an exotoxin from the organism Clostridum botulinum. The disease is characterized by progressive muscle weakness that can result in complete flaccid paralysis. Unfortunately, there is no known cure for the disorder. Botulinum neurotoxins are classified by the CDC as one of the six highest-risk threat agents for bioterrorism due to their relative ease of production, extreme potency and duration of paralytic activity. Countermeasures are needed to counteract the pathophysiology of BoNTs. To date there are no current interventions that can reverse the effects of intoxication after the toxin has reached its target inside the cell. As such the overarching goal of our proposal is to uncover molecules that can act within an intoxicated cell to provide symptomatic relief to BoNT/A. There are seven serologically distinct serotypes of BoNT, however, we will only focus on BoNT/A as it exhibits the most sustained intoxication and therefore represents the greatest threat of any of the BoNTs. Working within this framework we have taken a two-pronged approach to define such molecules. The first is based on small non-peptidic molecules that can inhibit the intracellular agent that causes neurotoxicity, a protease. For this initiative we will prepare mechanism-based inhibitors as well as team up with ASDI for the high throughput screening of the BoNT/A protease using their diversity collection and custom libraries to both discover new leads as well as enhance the potency of our previous lead compounds with confirmed anti-botulinum properties in vivo. Our second initiative relates to the discovery of molecules that will promote the release of acetylcholine in intoxicated cells. Our goal here are to find an intervention that could repair an intoxicated cell. To accomplish this aim we will take advantage of the known differences in potency based on their nerve terminal mechanism of action between BoNT/A-/E to devise a small molecule plan for neurotransmitter release from an intoxicated. In general we know relatively little about truly effective ways to counter toxin action at the 11th hour", and thus total reliance on any particular intervention is likely to be less than satisfactory. Furthermore, there is a vast difference in the time course of action of current potential antagonist and the toxin. This poses an enormous challenge in terms of discovery of agents for effective antagonism of BoNT/A poisoning. Against this backdrop our research will embrace the discovery of molecules that will provide both immediate and possible long-term relief from these neuroparalytic effects of BoNT/A. RELEVANCE (See instructions): Botulism poses an extreme threat to public health, primarily because of a complete lack of drugs available to combat this disease. Given the bioterrorism threat that botulinum neurotoxin poses, our proposal will develop new molecules to treat botulism and perform the studies needed to advance a potential drug into clinical trials.

描述（由申请人提供）：肉毒中毒是一种由肉毒杆菌外毒素引起的神经系统疾病。该病的特点是进行性肌肉无力，可导致完全弛缓性麻痹。不幸的是，目前还没有治愈这种疾病的方法。肉毒杆菌神经毒素被美国疾病控制与预防中心列为六种最高风险的生物恐怖主义威胁物质之一，因为它们相对容易生产，效力极强，并能持续瘫痪。需要采取对策来抵消BoNTs的病理生理。迄今为止，目前还没有干预措施可以在毒素到达细胞内的目标后逆转中毒的影响。因此，我们建议的总体目标是发现可以在中毒细胞内发挥作用的分子，从而为BoNT/A提供症状缓解。BoNT在血清学上有七种不同的血清型，然而，我们将只关注BoNT/A，因为它表现出最持久的中毒，因此是BoNT中最大的威胁。在这个框架下，我们采取了双管齐下的方法来定义这些分子。第一种是基于小的非肽分子，它可以抑制引起神经毒性的细胞内因子，一种蛋白酶。在这项计划中，我们将准备基于机制的抑制剂，并与ASDI合作，利用他们的多样性收集和定制文库对BoNT/A蛋白酶进行高通量筛选，以发现新的先导化合物，并增强我们之前的先导化合物的效力，这些先导化合物具有体内抗肉毒杆菌的特性。我们的第二个项目是发现一种分子可以促进中毒细胞释放乙酰胆碱。我们的目标是找到一种可以修复中毒细胞的干预方法。为了实现这一目标，我们将利用BoNT/A-/E之间基于其神经终端作用机制的已知效力差异来设计一个小分子计划，用于醉酒神经递质释放。总的来说，我们对在第11个小时对抗毒素作用的真正有效方法知之甚少，因此完全依赖任何特定的干预措施可能都不太令人满意。此外，当前潜在拮抗剂和毒素在作用时间上存在巨大差异。这对发现有效拮抗BoNT/A中毒的药物提出了巨大的挑战。在此背景下，我们的研究将包括发现分子，这些分子将为BoNT/A的神经麻痹效应提供即时和可能的长期缓解。相关性（见说明）：肉毒杆菌中毒对公众健康构成极大威胁，主要是因为完全缺乏可用于防治这种疾病的药物。鉴于肉毒杆菌神经毒素构成的生物恐怖主义威胁，我们的提案将开发新的分子来治疗肉毒杆菌中毒，并进行必要的研究，以推进一种潜在的药物进入临床试验。