目前临床使用的抗乙肝病毒（hepatitis B virus, HBV）药物存在停药“反跳”、病毒耐药等问题，使其应用受到限制。研究发现，苯基丙烯酰胺类、异芳基二氢嘧啶类和苯丙氨酸二肽类化合物分别作用于核心蛋白和热休克蛋白，在克服“反跳”或耐药方面具有一定的优势，且具有相似的药效团。基于此，本项目拟借鉴药效团融合策略，根据三类化合物药效团重叠程度的不同进行融合，设计合成具有干扰HBV核心蛋白组装和调节热休克蛋白表达双重作用的新型抗HBV化合物，并在此基础上进行结构修饰，从细胞、分子水平研究化合物的生物活性和作用机制，以期获得活性较好、能够调控HBV生命周期中的关键环节如HBV核心蛋白的组装及宿主细胞热休克蛋白HSC70和/或HSP90的表达的化合物，以克服现有抗HBV药物存在的“反跳”及耐药问题。本项目的成功实施可为抗HBV药物的研究提供新的思路，同时也为发现新型抗HBV候选新药打下良好的基础。

Nowadays, the anti-HBV agents used in clinical practice is not entirely satisfactory, because of their defects, such as the rebound phenomenon and HBV resistance. Previous research showed that phenylpropenamides, heteroaryldihydropyrimidines and MTS could target HBV core proteins and heat shock proteins respectively, thus exhibiting advantages in overcoming rebound phenomenon or HBV resistance. More importantly, their pharmacophores are similar. With these in mind, a series of novel anti-HBV agents were designed and synthesized based on fused pharmacophore approach. These anti-HBV agents could interfere HBV core protein and regulate the heat shock protein expression in host cells simultaneously, thus overcoming rebound phenomenon and HBV resistance. In addition, their bioactivities and action mechanism in cellular and molecular levels were conducted, including the effects of the active compounds on the assembly of HBV core protein and the expression of heat shock proteins (HSC70, HSP90) in host cells. The successful implementation of this project could provide a novel strategy for the design of novel anti-HBV drugs, and lay a good foundation for the development of innovative anti-HBV candidates.