埃博拉病毒（EBOV）引起的传染性疾病时有暴发。我们自主创新、独特桥环骨架的苦豆碱衍生物KD18在体内、体外均显示良好抗EBOV活性，初步作用机制显示其靶点在宿主细胞的溶酶体内。.本项目拟在一系列原创性工作基础上，一方面，以KD18为先导物，以抗EBOV活性为导向，针对分子中多个结构片断开展较为系统的结构修饰与优化，累计合成100余个的全新桥环类衍生物，阐明构效关系；扩充与拓展桥环化学与桥环物类型。通过体内药效、药代以及安全性等综合性评价，优选出治疗窗口宽、成药性高的候选物1-2个。此候选物具有广谱抗EBOV优势，为EBOV突发传染性疾病暴发的应急与防控做好战略物质储备。另一方面，以KD18或标记的活性分子为探针，探讨与寻找其作用靶标与结合模式，阐明作用机制，进而完成其抗EBOV的化学及化学生物学整体研究。以此丰富与发展桥环生物碱的抗病毒药用功能，使我国天然产物创新药物研究跨入世界前沿。

The outbreak of Ebola virus (EBOV) infectious disease happens frequently. Aloperine derivative KD18 which is innovative and bearing unique bridge-ring skeleton exhibited good anti-EBOV activity in vitro and in vivo, and it is shown that the lysosomes of host cell might be the target of drug action..On the one hand, based on a series of original work, this project will take KD18 as the leading compound and anti-EBOV activity as the guidance, systematic modification and optimization will be carried out on different structure fragments, more than 100 new derivatives are going to be designed and synthesized to elucidate the structure-activity relationship. This project will also enrich and develop endocyclic chemistry and its structural type. Through the comprehensive evaluations of preliminary pharmacokinetics, safety and pharmaceutical characters, 1-2 candidates with wide therapeutic window and good druggability will be selected for the further development. This candidate has an advantage of broad-spectrum anti-EBOV activity, and provides strategic material for the emergency response and prevention on EBOV infectious diseases. On the other hand, KD18 will be taken as the probe to explore its target and mechanism of action and clarify the mechanism of chemical biology. Furthermore, this project will complete the overall framework of chemistry and chemical biology research on their anti-EBOV activities. This project might greatly enhance our ability on innovative anti-virus drug development, and make our anti-virus research on natural products into the forefront of the world.