Triagonist Peptide Therapeutics for Neuroprotection

用于神经保护的三角肽疗法

基本信息

批准号：
10326283
负责人：
KRISHNA KUMAR
金额：
$ 25.96万
依托单位：
VELUM, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2023-09-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326283
关键词：
Acute Agonist Agreement Alzheimer&apos s Disease American Animal Experiments Animal Model Attenuated Behavioral Biological Assay Biological Process Blood Blood - brain barrier anatomy Blood Glucose Brain Brain Concussion Cell Death Cell model Cells Characteristics Chemicals Chronic Clinical Clinical Research Clinical Trials Consensus Defect Degenerative Disorder Development Diabetic Neuropathies Dipeptides Disease Disease Progression Drug Exposure Drug Kinetics Engineering Enzymes Etiology Evaluation FDA approved Future GIPR gene GLP-2 GLP-I receptor Gastric Inhibitory Polypeptide Glucagon Glucagon Receptor Glutamates Goals Head Hormones Idiopathic Parkinson Disease Improve Access In Vitro Injury Investigation Knowledge Laboratories Lead Legal patent Libraries Ligands Link Manufactured football Mediating Military Personnel Modification Molecular Morbidity - disease rate Motor Neuron Disease N-terminal Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Parkinson Disease Patients Peptide Hydrolases Peptide Library Peptides Pharmaceutical Preparations Pharmacodynamics Phase Prevention Property Public Health Publishing Receptor Activation Resistance Risk Rodent Model Side Site Soccer Sports Stream TBI treatment Therapeutic Traumatic Brain Injury Vascular Dementia age related age related neurodegeneration analog attenuation base behavioral study blood-brain barrier penetration chemical stability contact sports cost design effective therapy excitotoxicity exenatide gastric inhibitory polypeptide receptor glucagon-like peptide 1 glucose metabolism improved in vivo lead candidate liraglutide loss of function mild traumatic brain injury motor function improvement mouse model neuroinflammation neuron loss neuroprotection novel strategies peptide analog peptide drug peptide hormone analog pharmacokinetics and pharmacodynamics phase 2 study physical insult pre-clinical public health relevance receptor safety assessment screening therapeutic candidate therapeutic effectiveness translational pipeline

项目摘要

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.

项目摘要与神经元变性和功能障碍相关的发病率使公众越来越多健康伯恩。在导致神经元功能障碍的广泛病因中，包括阿尔茨海默氏症和帕金森氏病和血管痴呆等慢性疾病，一种在很大程度上没有注意到的主要原因，但越来越多地被认为是主要关心的是创伤性脑损伤（TBI）。即使是轻度TBI（MTBI），这是高度普遍且低估的在与运动相关的伤害中，尤其是在美式足球和足球和军队中，持久，有时是渐进的长期衰弱效果。现在有证据表明即使是单一的创伤性脑损伤，除了导致可逆的短期缺陷之外，也会沉淀或加速与年龄相关的其他神经退行性疾病实体，如上所述。未满足需求是开发一种神经保护或疾病改良的疗法，可以减慢或停止疾病进展。最近，一种合成的单体胡椒化合物，充当三个独立的激动剂受体（“三亚贡人”），GLP-1R（胰高血糖素样肽-1受体），GIPR（葡萄糖依赖性）胰岛素多肽受体）和胰高血糖素受体，该受体控制和直接葡萄糖代谢似乎具有有益的神经营养和神经保护作用，对在TBI和阿尔茨海默氏病。我们已经在此三亚贡辣椒的N末端发明了化学修饰赋予高化学稳定性，同时保存天然效力和效率。这些，这些以及其他依赖侧链附件的肽修饰为设计打开门专门设计的进一步改进的肽类似物，以促进进入大脑并保护神经元细胞。这样的化合物将提供候选疗法可以进入转化管道，将在随后的II期研究中追求最初专注于为MTBI开发治疗方法。我们将综合一个辣椒库，并选择高效力目标受体激活和最大程度地进入大脑。在筛选漏斗中进一步移动，候选人将是根据其从氧化应激和谷氨酸兴奋性诱导的细胞死亡，并基于药物诱导的小胶质细胞衰减神经炎症。一阶段可交付的可交付方式将是识别铅候选人和备份化合物。这些分子将为将来的II期研究提供基础，以进一步确定PK/PD，并探索用小鼠行为研究中的热有效性 MTBI的模型是临床前（和临床）研究的前奏。