Rupestonic Acid Derivative YZH-106 Promotes Lysosomal Degradation of HBV L- and M-HBsAg via Direct Interaction with PreS2 Domain

Rupestonic Acid Derivative YZH-106 Promotes Lysosomal Degradation of HBV L- and M-HBsAg via Direct Interaction with PreS2 Domain

Blog Article

Hepatitis B surface SHORT SLEEVE TOPS 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 TEPEZCO-BB CREME (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.