新宿主细胞靶标的发现对于对抗HCV耐药以及研发新型泛基因型抗HCV药物具有十分重要的意义。申请人前期研究中发现木豆素具有明显的抗HCV病毒活性，而且其对HCV 耐药株均体现出了与野生株相当的活性，与直接作用于病毒的抗HCV药物联用也体现出了对HCV病毒复制抑制的协同效应。初步的作用机制研究发现木豆素对常见病毒蛋白均无明显抑制作用，而是通过加速宿主细胞硫酸软骨素N-乙酰氨半乳糖胺基转移酶1（CSGalNAcT-1）的降解来抑制HCV病毒的复制。但是，与木豆素直接结合的宿主细胞蛋白还不得而知。因此，本课题拟采用化学蛋白质组学策略，找到直接与木豆素结合的蛋白，阐明这（些）蛋白与HCV病毒复制以及CSGalNAcT-1蛋白降解之间的关系。从而为新型泛基因型抗HCV药物的研发提供新靶标，并同时能加深我们对病毒和宿主细胞相互作用的了解，从而为HCV疫苗的研发提供新思路。

The discovery of novel cellular targets for anti-HCV agents is highly desirable for combating drug resistance and discovery of pan-genotypic anti-HCV agents. Our previous studies showed that cajanine possessed potent inhibitory activity against HCV replications, and exhibited the same magnitude of inhibitory activity against both the wild-type and drug-resistant HCV. In addition, cajanine also synergistically inhibited HCV replication with approved DAAs. Furthermore, the mechanism of action study revealed that cajanine inhibited HCV replications via down-regulating a cellular protein chondroitin sulfate N-acetylgalactosaminyltransferase 1(CSGalNAcT-1). However, the protein(s), which physically bind to cajanine, remains to be clarified. Consequently, we propose to find out such protein(s) by employing chemoproteomics strategy and illustrate the relationships of such protein(s) with the replication of HCV virus and the degradation of CSGalNAcT-1. The completion of this project will yield novel cellular targets for the discovery of new anti-HCV agents, and meanwhile, will enhance our understanding of the HCV-host interactions, and thereby provides new clues for the development of HCV vaccine.