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（由适用提供）：帕金森氏病（PD）是第二个最常见的神经退行性疾病，影响了美国超过100万人。 PD由于多巴胺能神经元死亡而导致大脑的化学多巴胺中的防御能力，诸如步行，写作和说话等运动造成困难。当前的PD疗法仅治疗症状，并且不会扭转导致多巴胺产生脑细胞死亡的潜在疾病过程。这种情况导致了对神经保护或神经染色的新策略的广泛关注。在实验室中修改疾病过程的最有前途的方法已减轻了被称为“生长因子”的内源性脑化学物质。几个生长因素表明，在PD动物模型中，能够扭转疾病过程。这些生长因素中有一些表现出足够的承诺，即在患有PD的人类的临床试验中已经对其进行了测试。此类生长因子的一个承诺是胡椒“分泌蛋白”血管活性肠肽（VIP）和垂体腺苷酸环化酶激活多肽（PACAP），它们在神经元生存，神经保护，神经保护，注射，注射和免疫调节中起着重要作用。 PACAP受到保护，免受PD啮齿动物模型中多巴胺能神经元的丧失，但仅在直接注射到大脑中。我们建议通过创建PACAP/VIP糖肽，即表面活性剂，潜在的半衰期在体内延伸，并且可以有效地越过血脑屏障（BBB），从而避免了这一困难。我们已经开发了一个新的技术平台来开发这些糖肽类似物，这些糖肽类似物显示出稳定性的提高，保持所需受体的潜在结合和有效性，并渗透到BBB。我们将基于PACAP和VIP，在CHO细胞中表达的PAC1，VPAC1和VPAC2受体进行一系列新型糖肽，并在全身施用后在神经保护性和神经保护性和神经遗传活性的动物模型中测试最有希望的化合物。我们将进一步完善我们通过“ shot弹枪”微透析的药物开发，可以随着时间的推移有效地量化药物的大脑水平，从而可以直接测量体内药物稳定性。这是通过多个碰撞诱导的片段质谱法（MSN）实现的。通过这种方式，我们希望生产一个或多个候选药物以进一步开发，最终导致人类使用和临床应用PD的批准。