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）： 在美国，中风是第三大死亡原因，迫切需要开发新的、安全有效的脑缺血疗法。局灶性脑缺血后迟发性神经元细胞死亡被激活的分子机制最近已被阐明，并已确定了可能的药物靶点。这些包括激活线粒体程序性细胞死亡途径（凋亡）的蛋白质，如Caspase-8及其蛋白质底物Bid。 Bid是一种促凋亡Bcl-2家族蛋白，当通过Caspase-8的切割激活时，其与线粒体膜相互作用并引发导致Caspase-3和-7激活的级联细胞事件，从而导致神经元细胞死亡。为开发脑卒中的新疗法提供药理学工具，我们提出鉴定和优化能够阻断或降低Caspase-3/7和8活性的非选择性有机小分子。支持我们的初步数据，我们还建议开发能够拮抗Bid的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剂和组合使用时的功效。我们的假设是，通过结合非选择性半胱天冬酶抑制剂与Bid拮抗剂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在很大程度上减弱。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，而且还具有直接翻译脑缺血性卒中新疗法的巨大潜力。 (End摘要）