Abstract
Despite recent progress in the development of hepatitis C virus (HCV) inhibitors, cost-effective antiviral drugs, especially among the patients receiving liver transplantations, are still awaited. Schisandra is a traditional medicinal herb used to treat a range of liver disorders including hepatitis for thousands of years in China. To isolate the bioactive compounds of schisandra for the treatment of HCV infection, we screened a schisandra-extracts library and identified a tetracyclic triterpenoid, schizandronic acid (SZA), as a novel HCV entry inhibitor. Our findings suggested that SZA potently inhibited pan-HCV genotype entry into hepatoma cells and primary human hepatocytes without interfering virus binding on cell surface or internalization. However, virion-cell fusion process was impaired in the presence of SZA, along with the increased host membrane fluidity. We also found that SZA inhibited the spread of HCV to the neighboring cells, and combinations of SZA with interferon or telaprevir resulted in additive synergistic effect against HCV. Additionally, SZA diminished the establishment of HCV infection in vivo. The SZA target is different from conventional direct-acting antiviral agents, therefore, SZA is a potential therapeutic compound for the development of effective HCV entry inhibitors, especially for patients who need to prevent HCV reinfection during the course of liver transplantations.
Highlights
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, with an estimated prevalence of 3% of the world’s population[1]
The tetracyclic triterpene SY-73, known as schizandronic acid (SZA) (Fig. 1f), inhibited both HCVcc infection and HCV pseudo-particles (HCVpp) entry by approximately 90% at a concentration of 20 μg/ml with low cytotoxicity (Fig. 1c–e), a potent entry inhibitor to be selected for further study
Heparin strongly reduced hepatitis C virus (HCV) attachment to the cell surface, while in the presence of SZA, no effect on virus binding was observed (Fig. 4b). These results indicate that SZA plays no role in the impairment of HCV binding to the host cell surface
Summary
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, with an estimated prevalence of 3% of the world’s population[1]. In 2014, the use of ledipasvir/ sofosbuvir (Harvoni) and the interferon-free regimen including a combination regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir tablets (Viekira Pak) was approved by the Food and Drug Administration (FDA) for treating genotype 1 patients[6,7,8] These therapeutic options of individual antiviral drugs are likely to result in resistance development and carry significant side effects[9]. In a phase I clinical trial, a combination therapy of multiple anti-oxidants including schisandra extracts reduced one order of magnitude of HCV RNA level in 25% of patients with chronic HCV infection in the study[18 ]. These promising results prompted us to identify the anti-HCV compounds from the fruit of schisandra. Schizandronic acid (SZA), a tetracyclic triterpene, extracted from the fruit of Schisandra sphenanthera Rehd. et Wils., inhibited pan-genotypic HCV entry into human hepatocytes by interfering with virion-cell membrane fusion
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