BIOUSIAN GLYCONEUROPEPTIDE AMPHIPATHS PENETRATE THE BBB

描述(申请人提供)：几十年来，具有神经活性的多肽对血脑屏障(BBB)的穿透一直是一个谜。研究表明，小肽(脑啡肽)的糖基化导致更稳定的糖肽，并以药理上有用的量穿透血脑屏障。机械学研究表明，大脑毛细血管内皮层的内吞作用负责运输。最近的研究表明，更大的多肽(内啡肽)能够在膜存在的情况下采用螺旋构象，并且也可以通过血脑屏障运输。这项建议旨在探索和开发糖基化强啡肽和内啡肽的运输和药理学，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聚集在一起，以利用合成有机、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测糖肽吸附对膜模型的影响，试图了解糖肽构象的影响，以及在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，以测试这些药物在炎症和神经病理性疼痛模型中的系统给药效果，以及阿片类药物介导的副作用(Gl转运、耐受/依赖等)。和焦虑/抑郁。 根据我们之前的研究和发表的关于Delta受体的论文，我们预测其中一些化合物将比吗啡类止痛药具有更好的疗效、更低的毒性和/或改善副作用。更重要的是，中心假设(糖基化策略可以应用于更大的多肽以提高中枢神经系统的生物利用度)将使用多学科方法进行严格测试。如果这一假设得到支持，这项技术可能会带来一种翻天覆地的平台技术，以此为基础，基于内源性神经肽的各种药物的临床开发。

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.