Lipoate Derivatives Targeting Alzheimer's Amyloid

靶向阿尔茨海默病淀粉样蛋白的硫辛酸衍生物

基本信息

  • 批准号:
    7256749
  • 负责人:
  • 金额:
    $ 20.72万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-08-01 至 2009-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The clinical benefits of current antioxidant/metal chelation therapies for Alzheimer's disease (AD), the most common form of senile dementia, are limited due to their poor disease target specificity. Moreover, the exact subserving mechanism(s) of antioxidant/metal chelation effects upon AD amyloid pathology are not clear. Our long-term objective is thus to design target-specific antioxidants/metal chelators and better understand their pharmacological mechanisms for AD and other human diseases, based on an emerging "pharmacophore conjugation" concept for drug development. The specific hypothesis for this proposal is that amyloid-targeting antioxidants/metal chelators assume targeted interdictions against cerebral A¿ amyloid pathology and associated oxidative stress. We have synthesized and characterized a novel bifunctional antioxidant- XH2 with chemically conjugated amyloid-binding (benzothiazole) and metal-chelating antioxidant (lipoate) moieties. We base the hypothesis on previous observations and current pilot data suggest that: (i) biometals such as Fe, Cu, Zn, which are strongly present in human amyloid plaques, promote A¿ amyloidosis and oligomerization that are mediated by reactive oxygen species (ROS) such as H2O2 and attenuated by catalase and metal chelators- DTPA and EDTA; (ii) XH2 molecule has only one NH group (<5 hydrogen-bond donors), two N and one O atoms (<10 hydrogen bond acceptors), MW=415 (<500), and the measured octanol/water partition coefficient = 2.1¿0.1 (<5). It agrees well with the general Lipinski's Rule of Five; (iii) XH2 interacts with A¿1-40 peptide computationally and has an affinity binding constant of KD=4.43 ¿M toward monomeric A¿1-40 peptide molecules in its freshly prepared solution; (iv) XH2 has no neurotoxicity at low micromolar concentrations, and it attenuates cerebral A¿ amyloid pathology in PS1/APP doubly transgenic mice without inducing apparent animal toxicity and behavior disturbances. We plan to test our current hypothesis and to achieve the objective of this application by pursuing the following three specific aims: 1. Determine the effects of XH2 upon A¿ neurotoxicity and APP translation in cell culture; 2. Determine XH2 binding constants for aggregated and mixed A¿1-40/42 peptides and blood-brain barrier (BBB) penetration of XH2; 3. Determine the effects of XH2 upon cerebral A¿ amyloid pathology, protein glutathionylation, and biometal profiles in amyloid plaques from PS1/APP transgenic mice. To achieve these specific aims, an array of experimental techniques such as surface plasmon resonance (SPR), LC/MS, SDS-PAGE, ELISA, semi-quantitative immunohistochemistry, laser capture microdissection (LCM) coupled with x-ray fluorescence microscopy (micro-XRM) techniques, and in vitro (human SH-SY5Y neuroblastoma and E17 primary rat cortical cells) and in vivo (PS1/APP doubly transgenic mouse) AD models, will be employed for the proposed studies. The overall rationale for the proposal is: our understanding about the molecular mechanism(s) and therapeutic values of amyloid-targeted antioxidants/chelators as potential AD-modifying agents need to be further clarified and validated.
描述(由申请人提供):目前抗氧化剂/金属螯合疗法治疗阿尔茨海默病(AD)(最常见的老年性痴呆)的临床获益有限,因为其疾病靶点特异性较差。此外,抗氧化剂/金属螯合作用对AD淀粉样蛋白病理学的确切保护机制尚不清楚。因此,我们的长期目标是设计靶向特异性抗氧化剂/金属螯合剂,并更好地了解其对AD和其他人类疾病的药理学机制,基于新兴的“药效团缀合”概念用于药物开发。这一建议的具体假设是,淀粉样蛋白靶向抗氧化剂/金属螯合剂假设针对脑A淀粉样蛋白病理和相关的氧化应激的靶向阻断。我们已经合成并表征了一种新的双功能抗氧化剂-XH 2与化学共轭淀粉样蛋白结合(苯并噻唑)和金属螯合抗氧化剂(lipoate)部分。我们基于先前的观察和当前的试验数据提出了这一假设:(i)生物金属如Fe、Cu、Zn强烈存在于人类淀粉样蛋白斑块中,促进由活性氧(ROS)如H2 O2介导并由过氧化氢酶和金属螯合剂- DTPA和EDTA减弱的A?淀粉样变性和寡聚化;(ii)XH 2分子只有一个NH基团(<5个氢键供体),两个N和一个O原子(<10个氢键受体),MW=415(<500),测得的辛醇/水分配系数= 2.1 ± 0.1(<5)。它与Lipinski的五个规则一致;(iii)XH 2与A 1-40肽相互作用,并且在其新鲜制备的溶液中对单体A 1 - 40肽分子具有KD=4.43 <$M的亲和结合常数;(iv)XH 2在低微摩尔浓度下没有神经毒性,并且它减弱脑A 1-40肽的活性。在PS1/APP双转基因小鼠的淀粉样蛋白病理学中没有诱导明显的动物毒性和行为障碍。我们计划通过追求以下三个具体目标来测试我们当前的假设并实现本申请的目标:1.在细胞培养中确定XH 2对A?神经毒性和APP翻译的影响; 2.确定聚集和混合的A ² 1-40/42肽的XH 2结合常数以及XH 2的血脑屏障(BBB)渗透; 3.确定XH 2对PS1/APP转基因小鼠脑淀粉样蛋白病理学、蛋白谷胱甘肽化和淀粉样蛋白斑块中生物金属谱的影响。为了实现这些特定的目标,一系列的实验技术,如表面等离子体共振(SPR),LC/MS,SDS-PAGE,ELISA,半定量免疫组织化学,激光捕获显微切割(LCM)与X射线荧光显微镜相结合,(micro-XRM)技术和体外(人SH-SY 5 Y神经母细胞瘤和E17原代大鼠皮质细胞)和体内(PS1/APP双转基因小鼠)AD模型将用于所提出的研究。该提案的总体依据是:我们对淀粉样蛋白靶向抗氧化剂/螯合剂作为潜在AD修饰剂的分子机制和治疗价值的理解需要进一步澄清和验证。

项目成果

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XUDONG HUANG其他文献

XUDONG HUANG的其他文献

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{{ truncateString('XUDONG HUANG', 18)}}的其他基金

Nanoneurotoxicity of Metal Oxide Nanomaterials and Neurodegeneration
金属氧化物纳米材料的纳米神经毒性和神经退行性变
  • 批准号:
    9912082
  • 财政年份:
    2017
  • 资助金额:
    $ 20.72万
  • 项目类别:
Lipoate Derivatives Targeting Alzheimer's Amyloid
靶向阿尔茨海默病淀粉样蛋白的硫辛酸衍生物
  • 批准号:
    7473116
  • 财政年份:
    2007
  • 资助金额:
    $ 20.72万
  • 项目类别:
BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS
生物金属、氧化应激和 AB 淀粉样变性
  • 批准号:
    6226985
  • 财政年份:
    2001
  • 资助金额:
    $ 20.72万
  • 项目类别:
BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS
生物金属、氧化应激和 AB 淀粉样变性
  • 批准号:
    6849720
  • 财政年份:
    2001
  • 资助金额:
    $ 20.72万
  • 项目类别:
BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS
生物金属、氧化应激和 AB 淀粉样变性
  • 批准号:
    6697088
  • 财政年份:
    2001
  • 资助金额:
    $ 20.72万
  • 项目类别:
BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS
生物金属、氧化应激和 AB 淀粉样变性
  • 批准号:
    6629186
  • 财政年份:
    2001
  • 资助金额:
    $ 20.72万
  • 项目类别:
BIOMETALS, OXIDATIVE STRESS, AND AB AMYLOIDOSIS
生物金属、氧化应激和 AB 淀粉样变性
  • 批准号:
    6499216
  • 财政年份:
    2001
  • 资助金额:
    $ 20.72万
  • 项目类别:
ZINC AND ALZHEIMERS AMYLOID CHEMISTRY
锌和阿尔茨海默症淀粉样蛋白化学
  • 批准号:
    2824436
  • 财政年份:
    1998
  • 资助金额:
    $ 20.72万
  • 项目类别:
ZINC AND ALZHEIMERS AMYLOID CHEMISTRY
锌和阿尔茨海默症淀粉样蛋白化学
  • 批准号:
    2590801
  • 财政年份:
    1997
  • 资助金额:
    $ 20.72万
  • 项目类别:
ZINC AND ALZHEIMERS AMYLOID CHEMISTRY
锌和阿尔茨海默症淀粉样蛋白化学
  • 批准号:
    2330183
  • 财政年份:
    1996
  • 资助金额:
    $ 20.72万
  • 项目类别:
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