朊病毒病是由朊蛋白的错误折叠和聚集引起的一类严重的神经退行性疾病，目前没有有效的治疗措施。本项目研究针对现在抗朊病毒药物研发策略存在的缺陷，以朊病毒病发生的分子机制为导向，拟结合多种分子模拟、药物设计手段和多种分析和生物活性测定方法从以下三个方面（1）稳定朊蛋白的天然构象；（2）解聚或重新模拟PrPSc; (3)模拟其保护性突变的功能，发现作用机制清楚、作用靶标明确的具有抗朊病毒活性的化合物和多肽类抑制剂。同时，结合现有抗朊病毒药物研发失败的原因，本项目研究还将在药物发现和设计过程中，提前结合多种AMDET性质计算方法评价和预测候选化合物的药代动力学性质，为抗朊病毒药物研发提供高质量的候选化合物，增加药物研发的成功率。本项目研究得到的结果将为寻找有效的治疗和抗击朊病毒病的药物以及合理的治疗策略奠定有价值的物质基础，对于预防、治疗发病机理相似的淀粉样变病也具有重要的理论和实际应用价值。

Prion diseases are a group of serious neurodegenerative diseases caused by prion misfolding and aggregation. At present, there are still no effective therapeutic strategy. Aiming at the drawbacks of anti-prion drug development strategy, this project will combine various molecular dynamics simulation, drug design and biological activity evaluation methods to find anti-prion compounds and peptides with clear mechanism and target from three aspects: (1) to stablize natural conformation of prion, (2) to disaggregate or re-model PrPSc or (3) to simulate the function of protective mutations based on the prion pathogenesis. At the same time, by considering the fail reasons of the present anti-prion therapeutic strategy，this project will also pre-evaluate the ADMET properties based on several computational methods in the drug discovery and design, to provide the high quality candidates and increase the successful rate of drug research. The obtained results of this project will provide foundation for searching effective medicine and reasonable therapeutic strategy to cure and fight against prion diseases. It also has important theory and application value for preventing and treating the amyloid-related diseases with similar pathogenesis.