Cell-Permeable Peptides for Mitochondrial Protection

描述(由申请人提供)： 该申请是对《计划公告》(PAR-02-138)的响应，该公告要求申请翻译研究中的探索性/发展性项目。这项建议旨在确定神经退行性疾病的候选疗法。我们最近发现了一种小的亲脂性阳离子多肽DAPL(DMT-D-Arg-Phe-Lys-NH2，其中DMT=2‘，6’-二甲基酪氨酸)，它是细胞通透性的，并选择性地针对线粒体。对分离的小鼠肝脏线粒体的初步研究表明，这种小肽可以防止线粒体通透性转变和肿胀，并减少活性氧的积累。通过防止线粒体功能障碍，这种多肽可能在治疗许多神经退行性疾病方面有潜在的用处。我们现在正在寻求短期支持，以进一步探索这种先导肽类似物在保护脑线粒体免受各种线粒体毒素侵害方面的药理作用，并发现这种肽的新类似物，可能直接导致针对特定神经疾病的治疗开发项目。我们的具体目标如下：1)检测DAPL保护钙超载、3-硝基丙酸(3NPA)、1-甲基-4-苯基吡啶离子(MPP)和叔丁基氢过氧化氢(TBHP)引起的线粒体功能障碍的能力；2)检测DAPL保护谷氨酸、3NPA、MPP和tBHP引起的细胞死亡的能力；3)与DAPL类似物进行构效关系(SAR)研究，以确定用于进一步临床前开发的最佳多肽类似物。这些探索性研究的结果将指导我们开展临床前动物研究，以评估DAPL类似物在治疗中风和各种神经退行性疾病方面的治疗潜力，包括帕金森氏病、亨廷顿病和阿尔茨海默病。动物研究的潜在合作者已经确定。

DESCRIPTION (provided by applicant): The application is submitted in response to the Program Announcement (PAR-02-138) requesting applications for exploratory/developmental projects in translational research. This proposal seeks to identify candidate therapeutics for neurodegenerative disorders. We have recently discovered a small lipophilic cationic peptide DAPL (Dmt-D-Arg-Phe-Lys-NH2, where Dmt = 2', 6'-dimethyltyrosine) that is cell permeable and selectively targets mitochondria. Preliminary studies with isolated mouse liver mitochondria have shown that this small peptide can protect against mitochondrial permeability transition and swelling, and reduce accumulation of reactive oxygen species. By protecting against mitochondrial dysfunction, this peptide may potentially be useful in the treatment of numerous neurodegenerative disorders. We are now seeking short-term support to further explore the pharmacology of this lead peptide analog in protecting brain mitochondria against various mitochondrial toxins, and to discover new analogs of this peptide that might lead directly to a therapy development project for a particular neurological disorder. Our specific aims are as follows: 1) To examine the ability of DAPL to protect mitochondria dysfunction caused by calcium overloading, 3-nitropropionic acid (3NPA), 1-methyl-4-phenylpyridium ion (MPP+), and t-butyl hydroperoxide (tBHP; 2) To examine the ability of DAPL to protect against cell death caused by glutamate, 3NPA, MPP +, and tBHP; 3) To carry out structure-activity relationship (SAR) studies with DAPL analogs to identify the optimal peptide analog for further preclinical development. The results from these exploratory studies will guide us to the development of preclinical animal studies for evaluating the therapeutic potential of DAPL analogs in the treatment of stroke and various neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Alzheimer's disease. Potential collaborators for the animal studies have already been identified.