PACAP/VIP Glycopeptide Agonists as Neuroprotective Therapies for Parkinson's Disease

PACAP/VIP 糖肽激动剂作为帕金森病的神经保护疗法

基本信息

批准号：
9145807
负责人：
ROBIN POLT
金额：
$ 43.25万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145807
关键词：
Adverse effects Affect Agonist Animal Model Binding Biological Assay Blood - brain barrier anatomy Brain Calcium Carbohydrates Categories Cell Line Cell Membrane Permeability Cells Central Nervous System Agents Characteristics Chemicals Chinese Hamster Ovary Cell Clinical Trials Corpus striatum structure Data Development Disease Disease model Dopamine Drug Design Drug Kinetics Drug Stability Drug Targeting Dynorphins Endorphins Enkephalins Evaluation Glycopeptides Growth Health Human Hydroxydopamines Image Inflammation Injection of therapeutic agent Laboratories Lesion Ligands Mass Spectrum Analysis Measurement Metabolic Methods Microdialysis Molecular Movement Mus Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurohormones Neuromodulator Neuropeptides Neurotransmitters Opioid Receptor PACAP27 PACAPR-1 protein Parkinson Disease Penetration Peptides Peripheral Permeability Pharmaceutical Preparations Pharmacology Play Process Property Rattus Research Design Rodent Model Role Route S Phase Safety Sampling Secretin Selection Criteria Series Serum Shotguns Site Solid Source Testing Therapeutic Time Treatment Efficacy Vasoactive Intestinal Peptide Walking Writing analog base brain cell clinical application design dopaminergic neuron drug candidate drug development falls glycosylation immunoregulation in vivo in vivo Model interest meetings neuron loss neuronal survival neuroprotection neurorestoration new technology novel overexpression peptide drug peptide hormone pituitary adenylate cyclase activating polypeptide receptor receptor binding scaffold screening small molecule success surfactant symptom treatment vasoactive intestinal peptide 2 receptor vasoactive intestinal peptide receptor 1

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the 2nd most common neurodegenerative disorder, affecting over 1 million people in the US. PD causes difficulties with movements such as walking, writing, and speaking that occur because of deficits in the chemical dopamine in the brain due to dopaminergic neuron death. Current therapies for PD only treat the symptoms and do not reverse underlying disease processes that cause dopamine-producing brain cells to die. This situation has led to widespread interest in new strategies of neuroprotection or neurorestoration. The most promising approaches to modifying the disease process in the laboratory have relied on endogenous brain chemicals known as "growth factors." Several growth factors have demonstrated the ability to reverse the disease process in animal models of PD. A few of these growth factors have shown sufficient promise that they have been tested in clinical trials in humans with PD. One promising set of such growth factors are the peptide "secretins" Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), which play important roles in neuronal survival, neuroprotection, inflammation and immunomodulation. PACAP is protective against the loss of dopaminergic neurons in rodent models of PD, but only after being injected directly into the brain. We propose to circumvent this difficulty by creating PACAP/VIP glycopeptides, which are surfactants, possess extended half-lives in vivo, and can efficiently cross the blood-brain barrier (BBB). We have developed a new technology platform to develop these glycopeptide analogues that show increased stability, maintain potent binding and efficacy at the desired receptor(s), and that penetrate the BBB. We will synthesize a series of novel glycopeptides based on PACAP and VIP, screen for activity at the PAC1, VPAC1 and VPAC2 receptors expressed in CHO cells, and test the most promising compounds in animal models of PD for neuroprotective and neurorestorative activity after systemic administration. We will further refine our drug development by "shotgun" microdialysis to efficiently quantify brain levels of our drugs over time, allowing direct measurement of drug stability in vivo. This is accomplished by multiple collision-induced fragmentation mass spectroscopy (MSn). In this way we hope to produce one or more drug candidates for further development, ultimately leading to approval for human use and clinical application in the treatment of PD.

描述（由申请人提供）：帕金森病 (PD) 是第二大常见的神经退行性疾病，在美国影响着超过 100 万人，由于化学物质缺陷，帕金森病会导致行走、书写和说话等运动困难。由于多巴胺能神经元死亡导致大脑中多巴胺的产生，目前的帕金森病治疗方法只能治疗症状，不能逆转导致产生多巴胺的脑细胞死亡的潜在疾病过程。在实验室中改变疾病过程的最有希望的方法依赖于被称为“生长因子”的内源性脑化学物质。一些生长因子已被证明能够在帕金森病的动物模型中逆转疾病过程。这些生长因子中的一种已显示出足够的前景，已在患有帕金森病的人类中进行了临床试验，其中一组有前景的生长因子是肽“促胰液素”血管活性肠肽（VIP）和垂体腺苷酸。环化酶激活多肽 (PACAP) 在神经元存活、神经保护、炎症和免疫调节中发挥重要作用，PACAP 可以防止 PD 啮齿动物模型中多巴胺能神经元的损失，但只有在直接注射到大脑后才能发挥作用。通过创建 PACAP/VIP 糖肽来克服这一困难，PACAP/VIP 糖肽是表面活性剂，在体内具有较长的半衰期，并且可以有效地穿过血脑屏障 (BBB)。技术平台来开发这些糖肽类似物，这些糖肽类似物表现出更高的稳定性，在所需受体上保持有效的结合和功效，并且能够穿透血脑屏障。我们将合成一系列基于 PACAP 和 VIP 的新型糖肽，筛选其活性。 PAC1、VPAC1和VPAC2受体在CHO细胞中表达，并在PD动物模型中测试最有前途的化合物在全身给药后的神经保护和神经恢复活性。我们的药物开发通过“鸟枪”微透析来有效地量化我们药物随时间的变化的大脑水平，从而可以通过多重碰撞诱导碎片质谱（MSn）直接测量药物的稳定性。一种或多种候选药物有待进一步开发，最终获得批准用于人类并临床应用于治疗帕金森病。