An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor

Abstract

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.

An Overview of Hepatitis B Virus Surface Antigen Secretion Inhibitors

“…HBsAg secretion has shown to be inhibited in both HBV integrated and transient transfected HepG2 cell lines as high as 70% and 90%, respectively. Similar HBsAg secretion inhibition has been also observed in a cell line infected with HBV expressing NTCP after NJK14047 treatment ( Kim et al, 2017 ). Higher dose of NJK14047 small molecule was needed for obtaining sufficient HBV viral DNA, mRNA, and viral particle production ( Kim et al, 2017 ).…”

“…Similar HBsAg secretion inhibition has been also observed in a cell line infected with HBV expressing NTCP after NJK14047 treatment ( Kim et al, 2017 ). Higher dose of NJK14047 small molecule was needed for obtaining sufficient HBV viral DNA, mRNA, and viral particle production ( Kim et al, 2017 ). The novelty of the study was to target cellular factors involved in HBV infection.…”

“…Biphenylamid non-nucleoside derivate, NJK14047, is active in inhibition of p38 MAPK ( Kim et al, 2017 ). Accordingly, NJK14047 has been shown the greatest p38 MAPK inhibitory effect highly correlated (85%) with HBsAg secretion inhibition.…”

“…For achieving to the ideal of HBsAg clearance, sustained HBsAg secreting cell lines and animal models have been used. Meanwhile, HBsAg secretion inhibition levels are always significantly lower in cell lines with integrated viral genome than that in other transiently transfected hepatoma cells ( Kim et al, 2017 ). This is because of constant expression of HBsAg, which is independent of virus itself.…”

p38 mitogen‐activated protein kinase impairment of innate immune cells is a characteristic feature of HBeAg‐negative chronic hepatitis B

“…In a HBV transfected cell line, Chang and colleagues have shown HBV replication to activate p38 MAPK, while p‐p38 MAPK pharmacological inactivation resulted in inhibition of HBV replication, as was demonstrated by inhibition of HBV protein secretion and RNA synthesis . In HBV transfected cells and HBV‐infected human hepatoma cells, inhibition of p38 MAPK by novel selective inhibitors correlated with suppression of HBsAg production, HBeAg secretion and HBV virus production, in addition to suppression of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV‐harbouring cells . In carcinoma cell lines, the presence of HBV x protein has been shown to exert anti‐apoptotic action and to induce mitogenic mechanisms via activation of p38 MAPK signalling …”