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: 8242825
• 负责人: TOBIN J DICKERSON
• 金额: $ 116.42万
• 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/8242825
• 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）：肉毒杆菌中毒是一种由肉毒杆菌外毒素引起的神经系统疾病。该疾病的特点是进行性肌肉无力，可导致完全弛缓性瘫痪。不幸的是，目前尚无已知的方法可以治愈这种疾病。肉毒杆菌神经毒素被疾病预防控制中心列为生物恐怖主义六种最高风险的威胁物质之一，因为它们相对容易生产，具有极高的效力和麻痹活性的持续时间。需要采取对策来抵消 BoNT 的病理生理学作用。迄今为止，当毒素到达细胞内的目标后，目前还没有任何干预措施可以逆转中毒的影响。因此，我们建议的首要目标是发现可以在中毒细胞内发挥作用以缓解 BoNT/A 症状的分子。 BoNT 有七种血清学上不同的血清型，但是，我们只关注 BoNT/A，因为它表现出最持久的中毒作用，因此代表了所有 BoNT 中最大的威胁。在这个框架内，我们采取了双管齐下的方法来定义此类分子。第一种是基于非肽小分子，可以抑制引起神经毒性的细胞内物质——蛋白酶。对于这一举措，我们将制备基于机制的抑制剂，并与 ASDI 合作，利用其多样性收集和定制库对 BoNT/A 蛋白酶进行高通量筛选，以发现新的先导化合物，并增强我们之前已证实具有体内抗肉毒杆菌特性的先导化合物的效力。我们的第二项举措涉及发现能够促进中毒细胞中乙酰胆碱释放的分子。我们的目标是找到一种可以修复中毒细胞的干预措施。为了实现这一目标，我们将利用基于 BoNT/A-/E 之间神经末梢作用机制的已知效力差异，设计一种小分子计划，用于醉酒者释放神经递质。一般来说，我们对在第 11 小时抵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干预措施可能不太令人满意。此外，当前潜在拮抗剂和毒素的作用时间过程存在巨大差异。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 这些分子将立即或可能长期缓解 BoNT/A 的神经麻痹作用。相关性（参见说明）：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对抗这种疾病的药物。鉴于肉毒杆菌神经毒素构成的生物恐怖主义威胁，我们的建议将开发新的分子来治疗肉毒杆菌中毒，并进行将潜在药物推进到治疗中所需的研究。 临床试验。