基于阻抑蛋白错误折叠的辽宁道地药材药效物质、分子机制及药代动力学研究

致病蛋白β-淀粉样蛋白(Aβ)和α-突触核蛋白(α-Syn)的错误折叠分别是神经变性构象病阿尔茨海默病和帕金森病的主要致病因素，以抑制致病蛋白错误折叠为药物靶点已成为神经药理学领域的前沿和热点。本项目拟采用“靶蛋白亲和色谱/HPLC-DAD-MS/MS”筛选系统，结合色谱学技术和波谱学方法对药材中的活性组分进行分离纯化及结构鉴定，发现辽宁道地药材中抑制蛋白错误折叠作用的药效物质；应用转基因小鼠模型，评价药效物质对Aβ和α-Syn错误折叠的抑制作用，获得新型的针对致病蛋白错误折叠为靶点的神经变性构象病前体药物，并探讨其潜在的多靶点机制；在明确药效物质和作用机制的基础上，进行药物代谢与动力学研究，分析其体内吸收、分布、代谢和排泄规律，为诠释传统中医药理论和指导中药材的临床合理化应用提供新思路。

Pathogenic protein misfolding is the major cause of neurodegenerative conformational disease. It is well-known that the misfolded β-amyloid protein (Aβ) and α-synuclein (α-Syn) are involved in Alzheimer’s disease and Parkinson’s disease, respectively. Recently, to inhibit the pathogenic protein misfolding as a drug target has become the frontier and hot spot in the field of neuropharmacology. In order to clarify the pharmacodynamic materials for protein misfolding inhibition in Liaoning geoherbs, we have set up a new “target protein affinity chromatography/HPLC-DAD-MS/MS” screening system. Guided by bioactivity screening, the herbal medicine active components were isolated and purified by chromatographic methods, and the structures were identified by spectral analysis. Using culture cells and transgenic mice, the inhibitory effect of single compound selected from geoherbs on Aβ and α-Syn misfolding will be evaluated both in vitro and in vivo. Hopefully, several lead compounds, which are based on inhibition of pathogenic protein misfolding, will be found from geoherbs. Meanwhile, the possible mechanism of multiple targets of lead compounds will be analyzed comprehensively. On the basis of clarifying the pharmacodynamic materials and mechanism, the pharmacokinetic study will be performed in order to analyze the in vivo absorption, metabolism and excretion of the selected pharmacodynamic materials from the geoherbs. The project will surely provide new ideas for the interpretation of the traditional Chinese medicine theory and the guidance of the clinical application of the Chinese herbal medicine.