Acetylcholinesterase Complex Protein-Protein Interactions as Drug Targets Against Organophosphate-induced Neurotoxicity.

乙酰胆碱酯酶复合物蛋白质-蛋白质相互作用作为抗有机磷诱导的神经毒性的药物靶点。

基本信息

  • 批准号:
    10303546
  • 负责人:
  • 金额:
    $ 22.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary. Organophosphate (OP) insecticides (e.g., chlorpyrifos, Naled, parathion) and chemical weapons (e.g., sarin, VX, Novichok) are potent inhibitors of acetylcholinesterase (AChE) that can trigger cholinergic crises presenting as muscle contractions, seizures, and in extreme exposures death. Particular OP compounds like parathion and sarin can rapidly (within minutes) irreversibly inhibit AChE, resulting in an “aged” enzyme that is refractory to existing AChE reactivators, namely 2-pralidoxime (2-PAM), which is part of the current OP treatment in the United States. Current strategies to reactivate aged AChE have shortcomings such as insufficient blood-brain barrier permeability and limited efficacy in vivo. Consequently, there is an urgent need to identify and refine novel approaches to rescue AChE activity following OP exposure to mitigate the damaging effects of OPs. The long- term goal of the proposed research is to develop viable, lasting treatments for acute and repeated OP exposures. Previous efforts to rescue aged AChE have focused on producing new classes of reactivators that will alkylate the phosphorylated enzyme allowing them to react with oximes like 2-PAM to recover enzyme function. The proposed research is innovative because it employs strategies aimed at increasing the turnover aged AChE and recovery of nascent intracellular AChE. For example, inhibiting or loss of muscle-specific protein kinase (MuSK) destabilizes the AChE complex leading to the degradation of the enzyme. Therefore, the current research objective is to assess whether targeting proteins in the synaptic AChE complex can increase AChE turnover and restore optimal AChE activity. The central hypothesis in pursuit of this objective is that inhibiting or degrading proteins associated with aged AChE will cause the release of the aged enzyme, making way for new AChE to repopulate the synapse, restore optimal neurotransmission, and mitigate the effects of OP exposures. The rationale for the proposed research is that eliminating aged AChE will alleviate the detrimental effects of OP toxicity and restore proper neurotransmission. Based on published and preliminary studies, the hypothesis will be investigated by undertaking the following specific aims: (1) Evaluate the in vitro therapeutic benefit of targeting proteins in the AChE complex for degradation, and (2) Examine the impact of acute MuSK inhibition on aged AChE levels and enzyme activity. In the first aim, Pz-1, a known inhibitor of MuSK shown in preliminary studies to induce turnover of aged AChE, will be used to treat Long-Evans rats exposed to diisopropyl fluoride (DFP), an OP known to age AChE quickly. Measures of DFP neurotoxicity, AChE levels, and cholinesterase activity recovery will be used to determine Pz-1 efficacy. In the second aim, individual proteins comprising the AChE will be selectively targeted for degradation using pharmacological approaches to assess the contribution of each protein to aged AChE stability in human cells, so that individual complex components may be evaluated as drug targets in future studies. This research is significant because it will provide fundamental mechanistic insights into the stability and turnover of post-synaptic AChE complexes and unearth new targets to treat OP exposures.
项目摘要。 有机磷酸酯(OP)杀虫剂(例如,毒死蜱、纳莱德、毒死蜱)和化学武器(例如,沙林毒气VX毒气 Novichok)是乙酰胆碱酯酶(AChE)的强效抑制剂,可引发胆碱能危象,表现为 肌肉收缩,癫痫发作,极端暴露会导致死亡特别的OP化合物,如氯吡格雷和 沙林可以迅速(在几分钟内)不可逆地抑制乙酰胆碱酯酶,导致一种“老化”的酶, 现有的乙酰胆碱酯酶再活化剂,即2-解磷定(2-PAM),这是目前美国OP治疗的一部分, States.目前激活老化AChE的策略存在不足,如血脑屏障不足 渗透性和有限的体内功效。因此,迫切需要识别和提炼小说 方法来挽救乙酰胆碱酯酶活性后OP暴露,以减轻OP的破坏性影响。很长的- 拟议研究的长期目标是为急性和反复OP暴露开发可行的,持久的治疗方法。 以前拯救老化乙酰胆碱酯酶的努力集中在生产新型的再活化剂, 磷酸化的酶允许它们与肟如2-PAM反应以恢复酶功能。的 拟议的研究是创新的,因为它采用的战略,旨在增加营业额老化乙酰胆碱酯酶, 新生细胞内AChE的恢复。例如,肌肉特异性蛋白激酶(MuSK)的抑制或丧失 使AChE复合物不稳定,导致酶降解。因此,目前的研究 目的是评估突触乙酰胆碱酯酶复合物中的靶向蛋白是否可以增加乙酰胆碱酯酶的周转, 恢复最佳AChE活性。追求这一目标的核心假设是, 与老化的乙酰胆碱酯酶相关的蛋白质将导致老化酶的释放,为新的乙酰胆碱酯酶让路, 重新填充突触,恢复最佳神经传递,并减轻OP暴露的影响。的 提出这项研究的理由是,消除老化的乙酰胆碱酯酶将减轻OP的有害影响 毒性和恢复正常的神经传递。根据已发表的和初步的研究,该假设将 通过承担以下具体目标进行研究:(1)评价靶向的体外治疗益处 AChE复合物中的蛋白质降解,以及(2)检查急性MuSK抑制对老年人的影响。 乙酰胆碱酯酶水平和酶活性。在第一个目标中,Pz-1,一种在初步研究中显示的已知MuSK抑制剂, 以诱导老化AChE的周转,将用于治疗暴露于二异丙基氟(DFP)的Long-Evans大鼠, 一个能快速老化乙酰胆碱酯酶的手术DFP神经毒性、乙酰胆碱酯酶水平和胆碱酯酶活性的测量 恢复率将用于确定Pz-1的功效。在第二个目标中,包含AChE的单个蛋白质将 使用药理学方法选择性地靶向降解,以评估每种药物的作用 蛋白质在人细胞中老化AChE的稳定性,使得单个复合物组分可以作为药物进行评估。 未来研究的目标。这项研究意义重大,因为它将提供基本的机械见解, 突触后乙酰胆碱酯酶复合物的稳定性和营业额,并发现新的目标,以治疗OP的曝光。

项目成果

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Jeremy Wayne Chambers其他文献

Jeremy Wayne Chambers的其他文献

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{{ truncateString('Jeremy Wayne Chambers', 18)}}的其他基金

Acetylcholinesterase Complex Protein-Protein Interactions as Drug Targets Against Organophosphate-induced Neurotoxicity.
乙酰胆碱酯酶复合物蛋白质-蛋白质相互作用作为抗有机磷诱导的神经毒性的药物靶点。
  • 批准号:
    10772738
  • 财政年份:
    2023
  • 资助金额:
    $ 22.13万
  • 项目类别:

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ACETYLCHOLINESTERASE INHIBITORS AND DEMENTIAS
乙酰胆碱酯酶抑制剂和痴呆症
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    2049153
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