Despite recent advances in therapeutic strategies against hepatitis B virus (HBV)
infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective
antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified
p38 mitogen-activated protein kinase (MAPK) as a possible target for
antiviral strategies against various viruses, including HBV. Here, a series of
biphenyl amides were synthesized as novel
p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV
surface antigen (
HBsAg) production by these compounds was positively correlated with
p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by
HBsAg production,
HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV
antigens and HBV particles from HBV genome-transfected cells and HBV-infected
sodium taurocholate cotransporting polypeptide-expressing human
hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic
RNA and covalently closed
circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of
HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for
viral infection.