Hepatitis B virus (HBV) is a member of the hepatitis virus family. Specifically, the virus consists of an outer lipid envelope and an icosahedral nucleocapsid core. The nucleocapsid contains viral DNA and DNA polymerase with reverse transcriptase activity. Besides, the virus is one of the smallest encapsulated animal viruses. HBV is a small DNA virus with unusual characteristics similar to retrovirus. Moreover, HBV replicates through RNA intermediates and can be integrated into the host genome. Furthermore, the unique characteristics of the HBV replication cycle endow the virus with a unique ability to persist in infected cells. According to the sequence comparison, HBV can be divided into eight genotypes, A to H.
Meanwhile, HBV is a part of double-stranded DNA virus, which can cause acute and chronic liver infection. DNA synthesis occurs in all eukaryotes and prokaryotes, as well as in some viruses. Nonetheless, the accurate synthesis of DNA is very important to avoid DNA mutation. After HBV envelope protein binds to cell receptors, HBV particles enter hepatocytes through endocytosis. And then nucleocapsid is released into the cytoplasm. Additionally, HBV nucleocapsid assembly begins in the cytoplasm. The extrahepatic manifestations of HBV infection include various forms of vasculitis, nephropathy, and arthritis. Importantly, they are usually relevant to circulating immune complexes in the host body. Key stages of the HBV life cycle are potential targets of new antiviral therapy, including capsulization, virion assembly, and HBV replication. Here, we will introduce a potent hepatitis B virus (HBV) replication non-nucleoside inhibitor, AT-130.
AT-130 is an HBV Replication (DNA Synthesis) Inhibitor.
Above all, AT-130 is a phenylpropenamide derivative. AT-130 inhibits the viral DNA synthesis with an IC50 of 0.13 uM. Particularly, AT-130 inhibits both wt and mutant HBV. AT-130 has anti-HBV activity in hepatoma cells.
Next in importance, AT-130 inhibits Wt HBV (IC50=2.4 μM), rtL180M HBV (IC50=9.8 μM), rtM204I HBV (IC50=35.6 μM). Obviously, AT-130 with 0.1-100 uM for 7 days causes dose-dependent inhibition of wt HBV replication in HepG2 cells transduced with HBV baculovirus. Interestingly, AT-130 2.5 uM, reduced encapsidated HBV DNA by 50% (IC50) and at 18.5 uM by 90% (IC90). AT-130 has no toxic to either HepG2 or Huh-7 cells at concentrations of up to 250 μM.
Once again, AT-130 does not inhibit HBV DNA synthesis by blocking the HBV endogenous DNA polymerase reaction directly in Huh 7 or HepG2 cells. At the same time, AT-130 inhibits HBV DNA replication in hepatoma cells. But it has no effect on viral DNA polymerase activity or core protein translation. AT-130 has no effect on total HBV RNA production but does reduce encapsidated RNA. By the way, AT-130 does not affect core protein or nucleocapsid production and the activity of the protein expression vector.
All in all, AT-130 is an HBV replication (DNA synthesis) inhibitor.
William E Delaney 4th, et al. Antimicrob Agents Chemother. 2002 Sep;46(9):3057-60.