Entecavir combined with furin inhibitor simultaneously reduces hepatitis B virus replication and e antigen secretion

Background: The antiviral therapy of chronic hepatitis B virus (HBV) infection pursues the twin goals, virological response (undetectable serum HBV DNA) and hepatitis B e antigen (HBeAg) serological response (serum HBeAg loss/seroconversion). It’s relatively difficult, however, to understand the serological response, specifically for nucleotide/nucleoside analogs. Furin, a proprotein convertase, is involved with HBeAg maturation. The suppression of furin using inhibitors accordingly reduces HBeAg secretion, but possibly enhances HBV replication. Therefore, the process in line with the mixture of nucleoside analog entecavir (ETV) and furin inhibitors to hinder HBV replication and HBeAg secretion concurrently were studied here.

Methods: The suppression of furin was performed using inhibitors decanoyl-RVKR-chloromethylketone (CMK) and hexa-D-arginine (D6R) or even the expression of furin inhibitory prosegment. The influence of furin suppression on HBV replication and also the aftereffect of CMK coupled with nucleoside analog entecavir (ETV) on HBV replication and HBeAg secretion was investigated in HepG2.2.15 cells. HBeAg level on television was detected using enzyme-linked immunosorbent assay. Intracellular viral antigens and HBV DNA were detected using Western and Southern blotting analyses, correspondingly.

Results: CMK, D6R and also the expression of inhibitory prosegment all considerably reduced HBeAg secretion, only CMK enhance HBV replication. Concordantly, only CMK publish-transcriptionally accrued cytosolic HBV replication-essential hepatitis B core antigen (HBcAg). The HBcAg-accumulating aftereffect of CMK was further discovered to be resulted from the redundant inhibitory impact on the trypsin-like activity of cellular proteasomes that handle HBcAg degradation. Furthermore, the viral replication-enhancing Hexa-D-arginine aftereffect of CMK was abrogated by ETV and ETV coupled with CMK reduced HBV replication and HBeAg secretion concurrently.

Conclusion: The suppression of furin itself doesn’t enhance HBV replication. Nucleotide/nucleoside analogs coupled with furin inhibitors can be a potential good way to realize the twin goals from the antiviral therapy for chronic hepatitis B later on.