HBV replication modulates host gene expression and induces oxidative stress. In this HepAD38 model early events (0-4 days) in the host cell after induction of HBV replication can be studied under strictly defined conditions.

Helioxanthin is a natural product that inhibits the replication of a number of viruses. We found that a previously undescribed helioxanthin analogue, 8-1, exhibited potent anti-hepatitis B virus (HBV) activity with little cytotoxicity. 8-1 suppressed both HBV RNA and protein expression, as well as DNA replication of both wildtype and 3TC-resistant virus. Time-course analyses revealed that RNA expression was blocked first after treatment with 8-1, followed by viral proteins, and then DNA. 8-1 inhibited the activity of all HBV promoters by decreasing the binding of hepatocyte nuclear factor 4 (HNF-4), HNF-3, and fetoprotein factor to the precore/core promoter enhancer II region. The amount of HNF-4 and HNF-3 was decreased posttranscriptionally by 8-1 in HBV-producing cells, but not in HBV-negative cells. Therefore, 8-1 suppresses HBV replication by posttranscriptional down-regulation of critical transcription factors in HBV-producing cells, thus diminishing HBV promoter activity and blocking viral gene expression and replication. This mechanism is unique and different from other anti-HBV compounds previously described.hepatocyte nuclear factors ͉ helioxanthin ͉ HBV promoters H epatitis B virus (HBV) infection is still a major world health problem despite the availability of an effective vaccine. Approximately 350 million people are chronically infected with the virus worldwide, including 1.25 million in the U.S. and Ͼ200 million in China. HBV infection can persist for the life of the host, often leading to severe consequences such as liver failure, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Currently, there is no treatment that completely eliminates the infection in all chronically infected patients. The approved chemotherapeutic treatments (i.e., lamivudine, adefovir, entecavir, and telbivudine) inhibit virus replication by targeting the viral DNA polymerase, and after long-term treatment development of drug-resistant virus becomes problematic. IFN-␣ is also clinically useful for HBV infection, but it has substantial side effects as well. Some nonnucleoside inhibitors have also been reported to inhibit HBV replication by interfering with nucleocapsid assembly (1). Nevertheless, the search for compounds with novel antiviral targets and mechanisms is still needed.A series of analogues of a nonnucleoside natural product, helioxanthin, were synthesized and exhibited a broad-spectrum of antiviral activity (2-4). Among those analogues, 5-4-2 and 8-1 (Fig. 1A), in addition to blocking hepatitis C virus [50% inhibitory concentration (IC 50 ) ϭ 1 and 10 M respectively], HIV (4 and 15 M), herpes simplex virus type 1 (0.29 and 1.2 M), Epstein-Barr virus (11 and Ͼ25 M), and human papilloma virus (0.2 and 5.8 M), were most potent against HBV replication (0.08 and 0.1 M). Because the cytotoxicity of 5-4-2 is comparatively higher than that of 8-1 (2), 8-1 was chosen for further investigation of its activity against HBV. We found that 8-1 potently inhibits HBV replication by an antiviral mechanism that has not been...

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Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus [i.e. herpes simplex virus type 1 (HSV-1), and type 2 (HSV-2), varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV)] infections. In recent years, several new guanosine analogues have been developed, including the 3-membered cyclopropylmethyl and -methenyl derivatives (A-5021 and synguanol) and the 6-membered D- and L-cyclohexenyl derivatives. The activity of the acyclic/carbocyclic guanosine analogues has been determined against a wide spectrum of viruses, including the HSV-1, HSV-2, VZV, HCMV, and also human herpesviruses type 6 (HHV-6), type 7 (HHV-7) and type 8 (HHV-8), and hepatitis B virus (HBV). The new guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) were found to be particularly active against those viruses (HSV-1, HSV-2, VZV) that encode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-induced TK. Marked antiviral activity was also noted with A-5021 against HHV-6 and with D- and L-cyclohexenyl G against HCMV and HBV. The antiviral activity of the acyclic/carbocyclic nucleoside analogues could be markedly potentiated by mycophenolic acid, a potent inhibitor of inosine 5'-monophosphate (IMP) dehydrogenase. The new carbocyclic guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) hold great promise, not only as antiviral agents for the treatment of herpesvirus infections, but also an antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transduced by the viral (HSV-1, VZV) TK gene.