Second Generation Small Molecule Inhibitors of Botulinum Neurotoxins

第二代肉毒杆菌神经毒素小分子抑制剂

基本信息

  • 批准号:
    7644602
  • 负责人:
  • 金额:
    $ 81.48万
  • 依托单位:
  • 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:
    2009-09-25 至 2014-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Botulinum neurotoxins (BoNTs) represent one of the most serious bioterror threats to our national security. Secreted by spore forming bacteria Clostridium botulinum, baratii, and butyricium, BoNTs are responsible for the flaccid paralysis associated with botulism. Listed as category A biothreats by the CDC, BoNTs are the most toxic of biological toxins, are easily produced, and may be delivered by various routes including food spiking (solid and liquid) and aerosol dispersion. There are no therapeutics to counter BoNT induced paralysis once the enzyme has entered the neuronal cytosol - at this time the only treatment option is impractical mechanical ventilation in a critical care setting. The long-term objective of this project is to address this public health threat by developing potent small molecule, non-peptidic, inhibitors (SMNPIs) of BoNTs as therapeutics that will serve as both rescue agents and prophylactics. Specific aims 1 - 3 of the proposal focus on translating our lead uM range SMNPIs of BoNT serotype A into low nM range SMNPIs that are effective in an animal model. Specific aim 4 concentrates on identifying and developing SMNPIs of BoNT serotype B that are effective in a neuronal assay, and specific aim 5 covers the identification of SMNPIs of BoNT serotype E. Finally, under specific aim 6, we propose examining all identified and developed SMNPIs for broad spectrum inhibitory activity against more than one BoNT serotype. To achieve the project goals we combine three-dimensional pharmacophore-based methods and synthetic organic chemistry strategies. Specifically, such methods combine X-ray crystallography, in vitro and in vivo biological testing, molecular modeling and 3-D database mining, and organic chemistry to guide SMNPI discovery and optimization (i.e., good in vitro potencies, good ADMET profiles, reduced toxicities, and enhanced in vivo efficacies in an animal model). RELEVANCE (See instructions): Botulinum neurotoxins (BoNTs) are the most potent toxins on the planet and are capable of being used as bioterror devises. There is currently no therapeutic to counter the inevitable suffocation and certain death resulting from the paralysis induced by BoNT poisoning. We propose the use of therapeutically viable chemicals as drugs. Our proposal includes molecules that already possess activity against critical components of the BoNT intoxication process for two serotypes.
描述(由申请人提供):肉毒杆菌神经毒素(BoNTs)是对我们国家安全最严重的生物恐怖威胁之一。bont由芽孢形成细菌肉毒梭菌、巴拉氏体和丁酸梭菌分泌,与肉毒中毒相关的弛缓性麻痹有关。bont被美国疾病控制与预防中心列为A类生物威胁,是生物毒素中毒性最大的,容易产生,并且可以通过各种途径传播,包括食物喷射(固体和液体)和气溶胶分散。一旦BoNT酶进入神经元细胞质,就没有治疗方法可以对抗BoNT诱导的瘫痪——此时唯一的治疗选择是在重症监护环境中不切实际的机械通气。该项目的长期目标是通过开发bont的有效小分子非肽抑制剂(smnpi)来解决这一公共卫生威胁,作为治疗药物,既可以作为拯救剂,也可以作为预防剂。该提案的具体目标1 - 3侧重于将我们的BoNT血清型A的uM范围smnpi转化为在动物模型中有效的低nM范围smnpi。特异性目标4专注于鉴定和开发在神经元试验中有效的B型BoNT血清型smnpi,特异性目标5涵盖鉴定e型BoNT血清型smnpi。最后,在特异性目标6下,我们建议检查所有已鉴定和开发的smnpi对多种BoNT血清型的广谱抑制活性。为了实现项目目标,我们将基于三维药物团的方法与合成有机化学策略相结合。具体来说,这些方法结合了x射线晶体学、体外和体内生物学测试、分子建模和3d数据库挖掘以及有机化学来指导SMNPI的发现和优化(即在动物模型中具有良好的体外药效、良好的ADMET谱、降低的毒性和增强的体内功效)。相关性(见说明):肉毒杆菌神经毒素(bont)是地球上最强大的毒素,能够被用作生物恐怖装置。目前还没有治疗方法来对抗由BoNT中毒引起的不可避免的窒息和某些死亡。我们建议使用治疗上可行的化学品作为药物。我们的建议包括已经对两种血清型BoNT中毒过程的关键成分具有活性的分子。

项目成果

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Sina Bavari其他文献

Sina Bavari的其他文献

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{{ truncateString('Sina Bavari', 18)}}的其他基金

Targeting Cellular Processes to Counter the Effects of BoNT Intoxication
靶向细胞过程来对抗 BoNT 中毒的影响
  • 批准号:
    8366888
  • 财政年份:
    2012
  • 资助金额:
    $ 81.48万
  • 项目类别:
Targeting Cellular Processes to Counter the Effects of BoNT Intoxication
靶向细胞过程来对抗 BoNT 中毒的影响
  • 批准号:
    8473162
  • 财政年份:
    2012
  • 资助金额:
    $ 81.48万
  • 项目类别:
Targeting Cellular Processes to Counter the Effects of BoNT Intoxication
靶向细胞过程来对抗 BoNT 中毒的影响
  • 批准号:
    9094670
  • 财政年份:
    2012
  • 资助金额:
    $ 81.48万
  • 项目类别:
Targeting Cellular Processes to Counter the Effects of BoNT Intoxication
靶向细胞过程来对抗 BoNT 中毒的影响
  • 批准号:
    8841460
  • 财政年份:
    2012
  • 资助金额:
    $ 81.48万
  • 项目类别:
Second Generation Small Molecule Inhibitors of Botulinum Neurotoxins
第二代肉毒杆菌神经毒素小分子抑制剂
  • 批准号:
    7938770
  • 财政年份:
    2009
  • 资助金额:
    $ 81.48万
  • 项目类别:
Second Generation Small Molecule Inhibitors of Botulinum Neurotoxins
第二代肉毒杆菌神经毒素小分子抑制剂
  • 批准号:
    8137145
  • 财政年份:
    2009
  • 资助金额:
    $ 81.48万
  • 项目类别:
Second Generation Small Molecule Inhibitors of Botulinum Neurotoxins
第二代肉毒杆菌神经毒素小分子抑制剂
  • 批准号:
    8316320
  • 财政年份:
    2009
  • 资助金额:
    $ 81.48万
  • 项目类别:
Second Generation Small Molecule Inhibitors of Botulinum Neurotoxins
第二代肉毒杆菌神经毒素小分子抑制剂
  • 批准号:
    8525316
  • 财政年份:
    2009
  • 资助金额:
    $ 81.48万
  • 项目类别:

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