Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules thatC hronic hepatitis B virus (HBV) infection, constituting a public health problem, with an estimated 240 million carriers worldwide (1), elevates the risk of development of liver cirrhosis and hepatocellular carcinoma (2). Antiviral agents against HBV include nucleos(t)ide analogs (NAs) and interferons (IFNs), which can achieve significant reductions in HBV loads (3). Although IFN-␣ and its pegylated form (peg-IFN-␣) modulate host immune responses to HBV infection or directly inhibit HBV replication in hepatocytes, these regimens show low tolerability because of serious adverse effects (3, 4). NAs, including lamivudine (LMV), adefovir, entecavir (ETV), tenofovir, and telbivudine, inhibit reverse transcription to suppress HBV replication, but longterm treatment with some of these NAs often results in selection for a significant number of drug-resistant viruses, which decreases treatment efficacy; i.e., the introduction of two substitutions, L180M and M204V, in the polymerase region leads to resistance to LMV, and an additional mutation of either T184, S202, or M250 with the L180M/M204V mutations confers further ETV resistance (5). More notably, it is difficult for the above-mentioned anti-HBV drugs to completely eliminate HBV from infected cells. Future antiviral strategies include multidrug treatment with an existing drug and a new anti-HBV agent. Consequently, there is a
Two new tricyclic polyketides, vanitaracin A (1) and B (2), together with three novel compounds 3, 4 and 5, were isolated from a culture broth of a fungus, Talaromyces sp. The chemical structures of these compounds were determined from spectroscopic data (1D/2D NMR, MS and IR). The five isolated compounds were then tested for anti-hepatitis B virus (HBV) activity and vanitaracin A was found to exhibit an IC50 value of 10.5 μM using a HBV-susceptible cell line. By contrast, the derivative 2 displayed weak anti-HBV action, which suggested that the substituents at C-9 in 1 are likely to be important for its antiviral activity. We believe the two vanitaracin derivatives constitute a new class of anti-HBV agents.
Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture. One of such compound, NPD8716, a coumarin derivative, interacted with NTCP and inhibited HBV infection without causing cytotoxicity. Consistent with its NTCP interaction capacity, this compound was shown to block viral attachment to host hepatocytes. NPD8716 also prevented the infection with hepatitis D virus, but not hepatitis C virus, in agreement with NPD8716 specifically inhibiting NTCP-mediated infection. Analysis of derivative compounds showed that the anti-HBV activity of compounds was apparently correlated with the affinity to NTCP and the capacity to impair NTCP-mediated bile acid uptake. These results are the first to show that the chemical array technology represents a powerful platform to identify novel viral entry inhibitors.
Two tricyclic polyketides, vanitaracin A (Ia) and B (Ib), and compounds (II), (III), and (IV) are isolated from a culture broth of title fungus and tested for their anti‐HBV activity.
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