以帕金森病(PD)为代表的神经退行性疾病严重威胁着人类健康，且目前没有理想的治疗药物。最新研究表明线粒体损伤和功能异常是PD发病的最主要原因，利用线粒体自噬清除受损线粒体，修复多巴胺能神经元是一个较好的干预手段，在PD模式动物中疗效确切。我们初期工作整合系统生物学方法，动物模型和临床样本组学分析，结合分子实验，证实了SIRT3在线粒体自噬和PD治疗中具有核心调控作用，并经过多轮筛选，发展了通过激活SIRT3诱导线粒体自噬并显示良好的抗 PD 效果的先导化合物SA-007。在本研究中，我们拟将前期得到的SA-007进行基于结构生物学的合理药物设计和化学修饰，研究其构效关系，以提高其对靶点的特异性及对线粒体功能修复和治疗PD的有效性。优选后化合物通过靶向SIRT3调控线粒体功能，对PD治疗和分子机制的阐述，可为线粒体自噬在神经退行性疾病中的功能研究和进一步探索全新治疗策略的抗PD药物奠定基础。

Parkinson's disease (PD) is one of the most common neurodegenerative disease, threatening human health seriously, and there are no effective drugs for its clinical use. Recent studies have suggested that mitochondrial injury and dysfunction are the main cause of Parkinson's disease. As a better means of intervention, mitophagy can protect and repair dopaminergic neurons by removing the damaged mitochondria, showing certain curative effect in several PD animal models. In our previous work, we used systems biology methods, clinical samples analyses and molecular pharmacology experiments to discover that acetylation enzyme SIRT3 plays a key role in regulation of mitophagy and PD treatment. After several rounds of screening, we discovered a lead compound SA-007, which has a good anti-PD effect through activating SIRT3 and inducing mitophagy. In this research project, we will synthesize a series of compounds by rational drug design and chemical modification based on structural biology, to study the structure-activity relationship, thus improving its target specificity and the effectiveness on mitophagy induction and PD treatment. Studies on the molecular mechanisms of anti-PD candidate compound can provide foundations for functional study of mitophagy in neurodegenerative diseases and further development of anti-PD drugs with novel treatment strategies.