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本帖最后由 风雨不动 于 2012-4-14 16:13 编辑
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Nitazoxanide, tizoxanide and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication...
There were 4 presentations at EASL. I'll be reporting them to you in detail.
Antiviral Research
Volume 77, Issue 1, January 2008, Pages 56-63
Hepatitis B virus (HBV)
Activities of compounds and combinations in 2.2.15 cell cultures
NTZ and its active metabolite, TIZ, exhibited selective inhibition of intracellular HBV replication and extracellular virus production by 2.2.15 cells (Table 1). Several other thiazolides (see Table 1) were also effective inhibitors of HBV replication in this assay system. Combinations of NTZ with either of two drugs licensed for anti-HBV therapy, lamivudine and adefovir dipovoxil, demonstrated synergistic interactions when used to treat 2.2.15 cells (Table 1, Fig. 2A and B). The anti-HBV assays were conducted under confluence as this provides the conditions for optimal HBV replication (Sells et al., 1988; Korba and Gerin, 1992). While under the conditions of the antiviral assay NTZ displayed minimal cytotoxicity (>100uM, Table 1), cytotoxicity of NTZ in rapidly dividing cultures of 2.2.15 cells was higher (20?.3uM). NTZ and RM4850 were effective inhibitors of several HBV LMV-resistant and one ADV-resistant constructs in transient transfection assays in Huh7 cells (Table 2). No significant differences in potency of these thiazolides relative to that observed for wild-type HBV were observed for any of the drug-resistant viruses tested.
Effect of NTZ on production of HBV proteins
Unlike most viruses (including HCV), HBV RNA transcription and protein production are effectively separated from viral genome replication due to the presence of a long-lived population of covalently closed viral template genomes in the host cell nucleus (cccDNA) (see Locarnini, 2004 for a review). Intracellular HBV replication takes place in viral nucleocapsids located in the cytoplasm. As a result, most compounds that inhibit HBV DNA replication (e.g. nucleoside analogues), do not typically alter HBV protein production, especially in cell culture. Suspecting a novel mechanism of action of NTZ against HBV, we conducted studies to determine if the drug inhibited the production of major HBV proteins. As assessed by semiquantitative EIA, NTZ reduced the levels of extracellular HBV surface and e antigens (HBsAg, HBeAg), as well as the levels of intracellular HBV nucleocapsid core antigen (HBcAg) in a dose-dependent manner (Table 3, Fig. 3). The potency of NTZ against HBsAg and HBeAg was similar to that observed against HBV virion production in the same experiment. The relative potency of NTZ against intracellular HBcAg was similar to that observed for the inhibition of intracellular HBV DNA replication. No quantitative interference with the ability of the EIAs to detect HBV proteins was observed in samples from control cultures to which 10 uMNTZ was added (data not shown).
NTZ did not induce a reduction in intracellular HBV RNA as assessed by Northern blot hybridization (Table 3, Fig. 3). In the same experiment, LMV did not affect the levels of HBV proteins or HBV RNA despite inducing significant reductions in HBV virion production and intracellular HBV DNA replication (Table 3).
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