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）： 中风代表了美国第三大死亡原因，即将开发新型，安全有效的脑缺血疗法。最近已经阐明了局灶性脑缺血后延迟神经元细胞死亡的分子机制，并已鉴定出可能的药物靶标。这些包括激活线粒体程序性细胞死亡途径（凋亡）的蛋白质，例如caspase-8及其蛋白质底物，bid。 竞标是一种促凋亡的Bcl-2家族蛋白，当通过caspase-8裂解激活时，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激活-7，以及随之而来的神经元细胞死亡。 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.最后，我们建议将化合物在用作单一药物和组合的动物模型中测试化合物在中风模型中的功效。我们的假设是，通过将非选择性caspase抑制剂与竞标拮抗剂相结合，通过阻止多个细胞死亡机制，将在很大程度上减弱代偿性细胞死亡途径的激活。我们的研究不仅将为验证拟议的药物靶标和我们的中心假设提供有价值的药物，而且还具有直接翻译的巨大潜力，以开发新的脑缺血性中风疗法。 （抽象的结尾）