Triagonist Peptide Therapeutics for Neuroprotection

项目摘要 与神经元变性和功能障碍相关的发病率越来越多地引起公众 健康负担。在导致神经元功能障碍的各种病因中，包括 一种慢性疾病，如阿尔茨海默氏症、帕金森氏病和血管性痴呆 在很大程度上没有被注意到但越来越被认为是一个主要关切的主要原因是 创伤性脑损伤(TBI)。即使是轻微的脑损伤(MTBI)，这是非常普遍和被低估的 在运动相关的伤害中，特别是在美式橄榄球和足球以及军队中，可能会有 持久的，有时是渐进性的，长期的衰弱效应。现在有证据表明 即使是单一的创伤性脑损伤，除了造成可逆的短期缺陷外，也可能导致 或加速上述与年龄相关的其他神经退行性疾病实体。未被满足的人 需要开发一种神经保护性或疾病修正疗法，以减缓或阻止疾病 进步。 最近，一种合成的单体多肽化合物作为三种不同类型的激动剂 受体(“三激动剂”)、GLP-1R(胰升糖素样肽-1受体)、GIPR(葡萄糖依赖) 促胰岛素多肽受体)和控制和引导血糖的胰高血糖素受体 新陈代谢，似乎具有有益的神经营养和神经保护作用 脑外伤动物模型的神经保护作用及行为缺陷的改善 阿尔茨海默氏症。 我们已经在这种三激动剂多肽的N端发明了化学修饰 具有很高的化学稳定性，同时保持天然效力和功效。此外，这些 而其他依赖于侧链连接的多肽修饰为设计打开了大门 进一步改进的肽激素类似物，专门设计成便于获得 保护大脑和保护神经细胞。这类化合物将提供候选疗法， 可以进入翻译管道，将在随后的第二阶段研究中进行，将 最初专注于开发一种治疗多发性脑损伤的方法。 我们将合成一个多肽文库，并选择用于高效靶向受体激活和 最大限度地利用大脑。进一步通过筛选漏斗，候选人将被 根据它们将神经细胞从氧化应激中拯救出来的能力和 谷氨酸兴奋毒性诱导的细胞死亡及基于药物诱导的小胶质细胞减弱 神经炎。第一阶段的交付成果是确定一名主要候选人和一名 后备大院。这些分子将为未来的第二阶段研究提供基础，以进一步 测定PK/PD，并在小鼠行为学研究中探讨治疗效果 作为临床前(和临床)研究前奏的mTBI模型。

Project Summary Morbidity associated with neuronal degeneration and dysfunction poses an increasing public health burden. Among the wide range of etiologies that result in neuronal dysfunction, including chronic conditions such as Alzheimer’s and Parkinson’s disease and vascular dementias, one major cause that has been largely unnoticed but is increasingly recognized as a major concern is traumatic brain injury (TBI). Even mild TBI (mTBI), which is highly prevalent and underestimated in sport related injuries especially in American football and soccer and in the military, can have persistent, and sometimes progressive, long-term debilitating effects. There is now evidence that even a single traumatic brain injury, beyond causing reversible short-term defects, can precipitate or accelerate age-related other neurodegenerative disease entities as noted above. The unmet need is to develop a neuroprotective or disease-modifying therapy that can slow or halt disease progression. Recently, a synthetic monomeric peptide compound that acts as an agonist for three separate receptors (“triagonist”), GLP-1R (glucagon-like peptide-1 receptor), GIPR (glucose-dependent insulinotropic polypeptide receptor) and the glucagon receptor that control and direct glucose metabolism, seems to have beneficial neurotrophic and neuroprotective effects useful for conferring neuroprotection and mitigating the behavioral deficits in animal models of TBI and Alzheimer’s disease. We have invented chemical modifications at the N-terminal end of this triagonist peptide that confer high chemical stability while conserving native potency and efficacy. Furtheremore, these and other peptide modifications that rely on side chain attachments open the door for the design of further improved peptide hormone analogs that are specifically designed to facilitate access to the brain and protect neuronal cells. Such compounds will provide candidate therapeutics that can move into the translational pipeline, to be pursued in subsequent phase II studies that will initially focus on developing a treatment for mTBI. We will synthesize a library of peptides and select for high potency target receptor activation and maximized access to the brain. Moving further through the screening funnel, candidates will be further prioritized based on their ability to rescue neuronal cells from oxidative stress and glutamate excitotoxicity–induced cell death, and based on drug-induced attenuation of microglial neuroinflammation. The deliverable in phase I will be the identification of a lead candidate and a backup compound. These molecules will provide the basis for future phase II studies to further determine PK/PD, and to explore therapeutic effectiveness in behavioral studies with mouse models of mTBI as a prelude to preclinical (and clinical) studies.