BIOUSIAN GLYCONEUROPEPTIDE AMPHIPATHS PENETRATE THE BBB

描述（由申请人提供）：几十年来，神经活性肽对血脑屏障（BBB）的渗透一直是一个谜。研究表明，小肽（脑啡肽）的糖基化导致更稳定的糖肽，并能以药理学上有用的数量穿透血脑屏障。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）能够在膜的存在下采用螺旋构象，并且也可以通过血脑屏障运输。本提案旨在探索和利用糖基化的肌啡肽和内啡肽肽的转运和药理学，并评估它们作为治疗慢性疼痛的候选药物。为了将合成有机、生物物理和药理学工具带到这个问题上，一个独特的研究小组已经集结起来。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的稳定性、转运速率和结合亲和力相关。最后，将在小鼠身上进行行为学研究，以测试系统给药对炎症性和神经性疼痛、阿片类药物介导的副作用（Gl转运、耐受/依赖等）和焦虑/抑郁模型的影响。

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.