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Abstract：
Hepatitis B surface antigen (HBsAg) is not only the biomarker of hepatitis B virus (HBV) infection and expression activity in hepatocytes, but it also contributes to viral specific T cell exhaustion and HBV persistent infection. Therefore, anti-HBV therapies targeting HBsAg to achieve HBsAg loss are key approaches for an HBV functional cure. In this study, we found that YZH-106, a rupestonic acid derivative, inhibited HBsAg secretion and viral replication. Further investigation demonstrated that YZH-106 promoted the lysosomal degradation of viral L- and M-HBs proteins. A mechanistic study using Biacore and docking analysis revealed that YZH-106 bound directly to the PreS2 domain of L- and M-HBsAg, thereby blocking their entry into the endoplasmic reticulum (ER) and promoting their degradation in cytoplasm. Our work thereby provides the basis for the design of a novel compound therapy to target HBsAg against HBV infection.
摘要：
乙型肝炎表面抗原（HBsAg）不仅是乙型肝炎病毒（HBV）感染和肝细胞表达活性的生物标志物，但它也有助于病毒特异性T细胞耗尽和HBV持续感染。因此,针对HBsAg实现HBsAg消失的抗HBV治疗是HBV功能治愈的关键方法。在这项研究中,我们发现YZH-106，一种雷公藤酸衍生物，抑制HBsAg分泌和病毒复制。进一步的研究表明，YZH-106促进病毒L-和M-HBs蛋白的溶酶体降解。使用Biacore和对接分析的机理研究表明，YZH-106直接结合到L-和M-HBsAg的PreS2域，从而阻断它们进入内质网(ER)并促进它们在细胞质中的降解。因此，我们的工作为设计针对HBV感染的针对HBsAg的新型复合疗法提供了基础。
