目前对帕金森病的治疗还没有特效药，已经上市的为数不多的药物都因为疗效不佳或毒副作用大较难满足要求。对PD发病机理的最新研究表明诱导细胞自噬可通过自噬溶酶体途径清除易聚蛋白，对神经元有保护和修复功能，在PD模式动物中治疗效果确切。我们的前期工作也利用系统生物学网络，证实ULK1(Unc-51激酶1)调控的自噬枢纽蛋白网络在PD疾病模型中占主导地位，并通过多轮系列筛选，发展了通过激活ULK1网络引起细胞自噬并显示较好的抗PD效果的小分子先导化合物U-007。在本研究计划中，我们拟将前期得到的U-007进行基于结构生物的合理药物设计和化学修饰，合成一系列化合物，研究构效关系，以提高其对ULK1的特异性及对自噬诱导和治疗PD的有效性，优选后的化合物在体内通过靶向ULK1自噬网络对PD的治疗效果和分子机制研究，可为细胞自噬在中枢神经退行性疾病中的功能研究和进一步开发全新治疗策略抗PD药物打下基础。

At present, the treatment of Parkinson's disease has no cure。 The few drugs already on the market is difficult to meet the requirements because of poor efficacy or side effects. The latest researches on pathogenesis of PD exhibite that inducing cell autophagy by autophagy-lysosome pathway can clear poly-protein, protect and repair the neurons and has definite therapeutic effect in the PD animal model. Our initial work used the systems biological network, and confirmed that ULK1 (Unc-51 kinase 1) hub protein network in autophagy regulation is dominant in the PD disease model. We developed the lead compound U-007 which can activate ULK1 autophagic network and show better anti-PD effect. In this research project, we plan to design and sythesize new U-007 derivatives based on structural biology and CADD. The synthesis of a series of compounds and structure-activity relationship are in order to improve the specificity of ULK1 and the effectiveness of autophagy induced by PD treatment. The PD therapeutic effect and molecular mechanism of preferred compound targeting ULK1 autophagic network can provide more informations for the functions of autophagy in the pathogenisis of neurodegenerative diseases and for the further development of new treatment strategies of anti-PD drugs.