SKI-1/S1P inhibition: A promising surrogate to statins to block Hepatitis C virus replication
INRS-Institut Armand-Frappier, Institut National de la Recherche Scientifique, Laval, Canada.Antiviral research (Impact Factor: 3.94). 05/2012; 95(2):159-66. DOI: 10.1016/j.antiviral.2012.05.006
Hepatitis C virus (HCV) is often associated with steatosis, cirrhosis and hepatocellular carcinoma (HCC). Statins (HMG-CoAR inhibitors) have been shown to exert an antiviral effect in vitro, principally on replicon harboring cells, but the effect of their use alone in vivo remains controversial. In clinical trials, when used in combination with the standards of care (SOC), they led to an increased proportion of sustained virological responder (SVR). Here we investigated the implication of SKI-1/S1P, a master lipogenic pathways regulator upstream of HMG-CoAR, on different steps of HCV life cycle. We compared the HCV antiviral effect of the most potent SKI-1/S1P small molecule inhibitor (PF-429242) with a set of two statins on different steps of the viral life cycle, and showed that SKI-1/S1P inhibitor blocked HCVcc (strain JFH-1) RNA replication (EC(50)= 5.8 μM) more efficiently than statins. Moreover, we showed that PF-429242 could reduce lipid droplets accumulation in Huh7 cells. Interestingly, PF-429242 dramatically reduced infectious particles production (EC(90)= 4.8 μM). Such inhibition could not be achieved with statins. SKI-1/S1P activity is thus essential for viral production and its inhibition should be considered for antiviral drug development.
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- "It is estimated that 130-170 million people have chronic HCV (about 3% of the world population). More than 3,00,000 people die every year from hepatitis C related liver diseases. There is no vaccination for HCV, so the treatment is very important. "
ABSTRACT: Background: Lipid metabolism is one of the hepatitis C virus (HCV) life cycle steps. Statins can reduce cholesterol level and finally can decrease HCV replication. Thus, we assessed the effect of Statins in combination with standard antiviral treatment on hyperlipidemic genotype I HCV infected patients. Materials and Methods: This study was a prospective clinical trial. 40 patients were selected from those referred to educational and Therapeutic Centers of Isfahan University of Medical Sciences from 2009 to 2010 with confirmed HCV viremia. All patients received Peg-interferon-a2a and ribavirin. 20 hyperlipidemic Patients received 20 mg atorvastatin nightly for 3 months and placebo was prescribed for 20 normolipidemic HCV infected patients as a control group. Liver enzymes and complete blood count were checked monthly and thyroid stimulating hormone was checked every 3 months. We also performed quantitative HCV-ribonucleic acid (RNA) test in 12th week of therapy, at the end of treatment and 6 months after therapy for all samples. Results: We didn’t find any significant differences in the mean of HCV-RNA numbers between statin and placebo groups in 12th week of treatment, in the end of treatment and 6 months after treatment (P > 0.05). Conclusion: Atorvastatin has no effect on the mean of HCV viral load when we added it to standard treatment for hepatitis C infection. Further studies are necessary to examine the possible antiviral properties of statins and their potential role as adjuncts to standard HCV therapy.
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ABSTRACT: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma worldwide. Furthermore, HCV-induced liver disease is a major indication of liver transplantation. In the past years, direct-acting antivirals (DAAs) targeting HCV enzymes have been developed. DAAs increase the virologic response to anti-HCV therapy but may lead to selection of drug-resistant variants and treatment failure. To date, strategies to prevent HCV infection are still lacking and antiviral therapy in immunocompromised patients, patients with advanced liver disease and HIV/HCV-co-infection remains limited. Alternative or complementary approaches addressing the limitations of current antiviral therapies are to boost the host's innate immunity or interfere with host factors required for pathogenesis. Host-targeting agents (HTAs) provide an interesting perspective for novel antiviral strategies against viral hepatitis since they have (i) a high genetic barrier to resistance (ii) a pan-genotypic antiviral activity and (iii) complementary mechanisms of action to DAAs and might therefore act in a synergistic manner with current standard of care or DAAs in clinical development. This review highlights HTAs against HCV infection that have potential as novel antivirals, are in clinical development, or are already in clinical use.
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ABSTRACT: The secretory proprotein convertase (PC) family comprises nine members: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9. The first seven PCs cleave their substrates at single or paired basic residues, and SKI-1/S1P cleaves its substrates at non-basic residues in the Golgi. PCSK9 cleaves itself once, and the secreted inactive protease escorts specific receptors for lysosomal degradation. It regulates the levels of circulating LDL cholesterol and is considered a major therapeutic target in phase III clinical trials. In vivo, PCs exhibit unique and often essential functions during development and/or in adulthood, but certain convertases also exhibit complementary, redundant, or opposite functions.
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