BIOUSIAN GLYCONEUROPEPTIDE AMPHIPATHS PENETRATE THE BBB

BIOUSIAN 糖欧洲肽两亲蛋白穿透血脑屏障

基本信息

批准号：
7795789
负责人：
ROBIN POLT
金额：
$ 30.63万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-10 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795789
关键词：
Adopted Adsorption Adverse effects Affinity Agonist Analgesics Anti-Anxiety Agents Antidepressive Agents Anxiety Area Arts Behavioral Behavioral Assay Benchmarking Binding Biodistribution Biological Biological Assay Biological Availability Biological Models Biotechnology Blood - brain barrier anatomy Blood capillaries Brain Carbohydrate Conformation Chronic Circular Dichroism Clinical Collaborations Comorbidity Coupled Data Dependence Development Diffusion Disease Dose-Limiting Drug Administration Routes Drug Delivery Systems Drug Design Drug Kinetics Dynorphins Endocytosis Endorphins Enkephalins Equipment Evaluation Evaluation Studies Functional disorder Glycopeptides Glycosides Goals Grant Human In Situ In Vitro Laboratories Lead Measures Mediating Membrane Mental Depression Methodology Methods Micelles Modeling Molecular Conformation Morphine Mus Neuropeptides Nuclear Nuclear Magnetic Resonance Opioid Opioid Analgesics Opioid Receptor Outcome Oxycodone Paper Partition Coefficient Pathology Penetration Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Pharmacopoeias Phase Physical Dependence Pre-Clinical Model Process Publishing Research Research Personnel Robin bird Rodent Model Role Running Sea Side Staging Structure Syndrome Techniques Technology Testing Therapeutic Toxic effect Ursidae Family Vertebral column Water addiction aqueous base capillary chronic pain delta opioid receptor design drug candidate drug development efficacy testing glycosylation improved in vivo inflammatory neuropathic pain interdisciplinary approach membrane model nervous system disorder neurochemistry non-cancer pain nuclear transfer pre-clinical programs rapid growth solid solution tool

项目摘要

DESCRIPTION (provided by applicant): The penetration of the blood-brain barrier (BBB) by neurologically active peptides has remained an enigmatic problem for many decades. Studies have shown that glycosylation of small peptides (enkephalins) leads to glycopeptides that are more stable, and which penetrate the BBB in pharmacologically useful amounts. Mechanistic studies have shown that endocytosis at the endothelial layer of the brain capillaries is responsible for transport. Recent studies indicate that much larger peptides (endorphins) are capable of adopting helical conformations in the presence of membranes, and are also transported across the BBB. This proposal seeks to explore and exploit the transport and pharmacology of glycosylated dynorphin and endorphin peptides, and to evaluate them as candidates for the treatment of chronic pain. A unique group of investigators has been assembled in order to bring synthetic organic, biophysical, and pharmacological tools to bear on this problem. Solution and solid phase NMR techniques will examine the effects of glycopeptide adsorption to membrane models, seeking to understand the effects on glycopeptide conformation, as well perturbations of the membrane during adsorption. Data from these studies will be correlated with glycopeptide stability, transport rates, and binding affinities. Finally, behavioral studies in mice will be carried out to test the effects of systematic administration of these drugs in models of inflammatory and neuropathic pain, opioid-mediated side effect (Gl transit, tolerance/dependence, etc.) and anxiety/depression. Based on our previous research and published papers on delta receptors, we predict that some of the compounds will have better efficacy, reduced toxicity and/or improved side effect profiles compared to morphine-like analgesics. More importantly, the central hypothesis (that glycosylation strategies can be applied to larger peptides to increase CNS bioavailability) will be rigorously tested using a multidisciplinary approach. If the hypothesis is supported, the technology may lead to a sea-changing platform technology on which to base the clinical development of diverse pharmaceuticals based on endogenous neuropeptides.

描述（由申请人提供）：神经活性肽对血脑屏障（BBB）的穿透几十年来一直是一个神秘的问题。研究表明，小肽（脑啡肽）的糖基化会产生更稳定的糖肽，并以药理学有用的量渗透血脑屏障。机制研究表明，脑毛细血管内皮层的内吞作用负责运输。最近的研究表明，更大的肽（内啡肽）能够在膜存在的情况下采用螺旋构象，并且也可以跨血脑屏障转运。该提案旨在探索和利用糖基化强啡肽和内啡肽的转运和药理学，并评估它们作为治疗慢性疼痛的候选药物。一个独特的研究小组已经成立，以便利用合成的有机、生物物理和药理学工具来解决这个问题。溶液和固相核磁共振技术将检查糖肽吸附对膜模型的影响，试图了解对糖肽构象的影响，以及吸附过程中膜的扰动。这些研究的数据将与糖肽稳定性、转运速率和结合亲和力相关。最后，将进行小鼠行为研究，以测试系统施用这些药物在炎症和神经性疼痛、阿片类药物介导的副作用（胃肠道转运、耐受/依赖性等）和焦虑/抑郁模型中的效果。根据我们之前关于 δ 受体的研究和发表的论文，我们预测与吗啡类镇痛药相比，某些化合物将具有更好的功效、更低的毒性和/或改善的副作用。更重要的是，中心假设（糖基化策略可以应用于更大的肽以增加 CNS 生物利用度）将使用多学科方法进行严格测试。如果这一假设得到支持，该技术可能会带来翻天覆地的平台技术，以此为基础进行基于内源性神经肽的多种药物的临床开发。