Anti-apoptotic compounds for treatment of brain ischemia

用于治疗脑缺血的抗凋亡化合物

• 批准号: 7008375
• 负责人: Maurizio Pellecchia
• 金额: $ 47.75万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008375
• 关键词: BCL2 gene /protein; apoptosis; brain disorder chemotherapy; cerebral ischemia /hypoxia; combinatorial chemistry; cysteine endopeptidases; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; laboratory rat; neural degeneration; neuropathology; neuroprotectants; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; protease inhibitor; small molecule; stroke therapy; therapy design /development; tissue /cell culture

DESCRIPTION (provided by applicant): With stroke representing the third leading cause of death in the United States, there is an impending need for the development of novel, safe and effective therapies for cerebral ischemia. The molecular mechanisms by which delayed neuronal cell death following focal cerebral ischemia is activated have been recently elucidated and possible drug targets have been identified. These include proteins that activate mitochondrial programmed cell death pathways (apoptosis) such as Caspase-8 and its protein substrate, Bid. Bid is a pro-apoptotic Bcl-2 family protein that when activated by cleavage by Caspase-8 interacts with the mitochondrial membrane and initiates a cascade of cellular events that lead to the activation of Caspase-3 and -7 and consequent neuronal cell death. With the goal of providing pharmacological tools for development of novel therapies for cerebral stroke, we propose to identify and optimize non-selective small organic molecules capable of blocking or reducing the activity of Caspases-3/7 and 8. Supported by our preliminary data, we also propose to develop small organic molecules that are capable of antagonizing the pro-apoptotic activity of Bid. Finally, we propose to test the efficacy of our compounds in animal models of stroke when used as single agents and in combination. Our hypothesis is that by blocking multiple cell-death mechanisms by means of combining non-selective Caspase inhibitors with Bid antagonists, the activation of compensatory cell-death pathways post-cerebral ischemia will be largely attenuated. Our studies not only will provide valuable agents for the validation of the proposed drug targets and our central hypotheses but also hold great potential for a direct translation in the development of novel therapies for cerebral ischemic stroke. (End of Abstract)

描述（由申请人提供）： 由于中风是美国第三大死因，因此迫切需要开发新颖、安全且有效的脑缺血疗法。最近阐明了局灶性脑缺血后延迟性神经细胞死亡被激活的分子机制，并且已经确定了可能的药物靶标。其中包括激活线粒体程序性细胞死亡途径（细胞凋亡）的蛋白质，例如 Caspase-8 及其蛋白质底物 Bid。 Bid 是一种促凋亡 Bcl-2 家族蛋白，当被 Caspase-8 裂解激活时，它会与线粒体膜相互作用，并启动一系列细胞事件，导致 Caspase-3 和 -7 的激活以及随后的神经元细胞死亡。为了为脑中风新疗法的开发提供药理学工具，我们建议识别和优化能够阻断或降低 Caspases-3/7 和 8 活性的非选择性小有机分子。在我们的初步数据支持下，我们还建议开发能够拮抗 Bid 促凋亡活性的有机小分子。最后，我们建议测试我们的化合物在中风动物模型中作为单一药物和组合使用时的功效。我们的假设是，通过将非选择性 Caspase 抑制剂与 Bid 拮抗剂相结合来阻断多种细胞死亡机制，脑缺血后代偿性细胞死亡途径的激活将大大减弱。我们的研究不仅将为验证所提出的药物靶点和我们的中心假设提供有价值的药物，而且还具有直接转化脑缺血性中风新疗法开发的巨大潜力。 （摘要完）