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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：
8445323
负责人：
TOBIN J DICKERSON
金额：
$ 110.19万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445323
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 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 screening 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(申请人提供)：肉毒杆菌中毒是一种由肉毒梭菌的外毒素引起的神经系统疾病。这种疾病的特点是进行性肌肉无力，可导致完全松弛瘫痪。不幸的是，目前还没有治愈这种疾病的已知方法。肉毒杆菌神经毒素被疾控中心列为生物恐怖主义的六种最高风险威胁因子之一，因为它们相对容易生产，具有极高的效力和瘫痪活动的持续时间。需要采取对策来对抗BoNTs的病理生理学。到目前为止，还没有任何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，我们建议的首要目标是发现可以在醉酒细胞内发挥作用的分子，以缓解BONT/A的症状。然而，BONT有七种不同的血清型，我们只关注BONT/A，因为它表现出最持久的醉酒，因此代表了任何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这种分子。第一种是基于小的非肽分子，可以抑制导致神经毒性的细胞内因子，一种蛋白酶。对于这一举措，我们将准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，并增强我们先前已证实具有体内抗肉毒杆菌特性的先导化合物的效力。我们的第二项倡议与发现促进醉酒细胞释放乙酰胆碱的分子有关。我们的目标是找到一种可以修复醉酒细胞的干预方法。为了实现这一目标，我们将利用已知的基于BONT/A-E之间的神经末梢作用机制的效力差异来设计一个小分子计划，用于从醉酒的人中释放神经递质。一般来说，我们对在11小时内对抗毒素行动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不太令人满意。此外，目前潜在的拮抗剂和毒素的作用时间进程也有很大的不同。这对寻找有效拮抗BoNT/A中毒的药物构成了巨大的挑战。在此背景下，我们的研究将包括分子的发现，这些分子将提供即时和可能的长期缓解这些神经麻痹效应的BONT/A。相关性(见说明)：肉毒杆菌中毒对公共健康构成极端威胁，主要是因为完全缺乏可用于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，我们的提议将开发新的分子来治疗肉毒杆菌中毒，并进行必要的研究，以推动潜在药物进入临床试验。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

8-Hydroxyquinoline and hydroxamic acid inhibitors of botulinum neurotoxin BoNT/A.

DOI：
10.2174/1568026614666141022095114
发表时间：
2014-08
期刊：
Current topics in medicinal chemistry
影响因子：
3.4
作者：
T. Dickerson;Garry R. Smith;J. Pelletier;A. Reitz
通讯作者：
T. Dickerson;Garry R. Smith;J. Pelletier;A. Reitz

Identification of clinically viable quinolinol inhibitors of botulinum neurotoxin A light chain.

DOI：
10.1021/jm4012164
发表时间：
2014-02-13
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Caglič D;Krutein MC;Bompiani KM;Barlow DJ;Benoni G;Pelletier JC;Reitz AB;Lairson LL;Houseknecht KL;Smith GR;Dickerson TJ
通讯作者：
Dickerson TJ

A bacteriophage-based platform for rapid trace detection of proteases.