Small Molecule Therapeutics for Botullinum Neurotoxin A

A 型肉毒杆菌神经毒素的小分子疗法

基本信息

批准号：
7797686
负责人：
TOBIN J DICKERSON
金额：
$ 119.18万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
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/7797686
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 Program Development Property Protein Binding Public Health Recovery Relative (related person)Reliance Research Research Institute Roentgen Rays Route 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 protein protein interaction repaired response small molecule small molecule libraries subcutaneous tool

项目摘要

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）：肉毒杆菌是由肉毒乳梭菌的外毒素引起的神经系统疾病。该疾病的特征是进行性肌肉无力，可能导致完全脆性瘫痪。不幸的是，没有已知的治疗方法。 CDC将肉毒杆菌神经毒素分类为生物恐怖主义的六种最高风险威胁药之一，因为它们相对易于生产，极端效力和麻痹活性的持续时间。需要对策来抵消BONT的病理生理学。迄今为止，没有目前的干预措施可以扭转毒素在细胞内的靶标的目标之后。因此，我们提案的总体目标是发现可以在陶醉的细胞内作用的分子，以减轻对BONT/A的症状缓解。 BONT有七个血清学不同的血清型，但是，我们只会专注于BONT/A，因为它表现出最持续的中毒，因此代表了任何BONT的最大威胁。在此框架内工作，我们采取了两种依据的方法来定义此类分子。第一个基于小的非肽分子，可以抑制引起神经毒性（蛋白酶）的细胞内剂。为此，我们将准备基于机制的抑制剂，并与ASDI合作，使用其多样性收集和自定义库对BONT/A蛋白酶进行高吞吐量筛选，以发现新的潜在客户，并增强我们先前的铅化合物的效力，并具有确认的抗Botulinum in Vivo。我们的第二个倡议与发现将促进陶醉细胞中乙酰胆碱释放的分子有关。我们的目标是找到可以修复陶醉的细胞的干预措施。为了实现这一目标，我们将基于BONT/A-/E之间的神经终末作用机理在效力上的已知差异，以设计从醉酒中释放神经递质的小分子计划。一般而言，我们对在第11个小时反对毒素作用的真正有效方法相对较少知道”，因此，完全依赖任何特定干预措施的可能性可能不足。此外，当前的潜在拮抗剂和毒素的时间过程中存在巨大差异。这在对反应的抗逆转录中的巨大挑战中构成了巨大的反应，这是对伯特（Bot）的巨大挑战，这是对伯特（Bot）的有效构成的。分子将立即从这些神经分析效应/a的神经分析作用（请参阅说明）：肉毒杆菌对公共健康构成极端威胁，这主要是因为完全缺乏可用的药物来抗击这种疾病，鉴于生物疾病的疾病会导致肉毒杆菌神经毒素构成。临床试验。