乙肝是危害全球尤其是我国的重要传染性疾病。疫苗虽可从源头上阻止乙肝病毒(HBV) 感染,但对于HBV患者尚缺乏特效药物。前期，在 NSFC (21002105, 81473121)支持下，我们基于天然产物合成的倍半萜衍生物PA-XY2能有效抑制HBV(IC50:10nM)。继而，发现其在20mg/kg剂量下非常显著地抑制HBV感染，明显减轻炎性细胞浸润程度，改善小鼠生存状态，具有进一步研究前景。但是，PA-XY2深入的作用机制和具体的作用靶点等尚需阐明。为此本项目将通过构建分子探针标记靶标蛋白等力争阐明PA-XY2的作用机制和作用靶点；在作用机制和靶点清晰的基础上，进一步借助衍生物合成手段开展PA-XY2全面的构效关系和构效再优化研究。最后对PA-XY2的系列衍生物开展成药性研究，发现新型抗HBV药物分子，为研制临床新一代的有自主知识产权的抗HBV感染的药物奠定重要基础。

Hepatitis B virus (HBV) infection is one of the major diseases in the world, especially in China. At present, HBV vaccine is an effective means to prevent HBV infection from the source. However, drugs for patients infected with HBV are unavailable. Under the support of the project (NSFC 21002105, and 81473121), we found norbisabolane sesquiterpenoid derivatives with anti-HBV activity firstly. Then we modified them to get PA-XY2 with in vitro potential anti-HBV activity (IC50: 10 nM; SI>50000). PA-XY2 in vivo could also effectively inhibit HBV infection at 20 mg/kg dose (SI>100). However, mechanism and target of PA-XY2 is unavailable. Therefore, we will constructed the small molecular probe to label the target protein in order to clarify the mechanism and target of PA-XY2. On basis of the aforementioned data, further structural optimization of PA-XY2 will studied on, as well as the structure-activity relationship of PA-XY2. The drug metabolism and pharmacokinetic (DMPK) of derivatives of PA-XY2 will be carried out in vitro and in vivo for developing new anti HBV drug molecules.