SKI-1/S1P inhibition: a promising surrogate to statins to block hepatitis C virus replication.
ABSTRACT 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.
- SourceAvailable from: Georgios Grammatikos[Show abstract] [Hide abstract]
ABSTRACT: Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, whereas combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. We conducted a literature search to identify trials that included monoinfected HCV patients, treated with statins or fibrates as monotherapy with the primary end point of our meta-analysis being the quantitative change of HCV-RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CIs) were calculated according to the DerSimonian-Laird estimate. Statistical heterogeneity was assessed with the I² statistic. We identified eight observational studies that evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV-RNA in HCV-monoinfected patients (n = 281). Overall, a significant reduction of viral load with mean 0.19 [log10 IU/mL] (95%-confidence interval, (CI) 0.11-0.28) could be observed when antihyperlipidemic medications were administered. Bezafibrate featured the highest antiviral efficacy (0.45 log10 reduction, 95%-CI, 0.17-0.72) among all medications and fluvastatin (0.20 log10 reduction, 95%-CI, 0.09-0.31) among all statins tested. Based on meta-analysis, fibrates and statins induce a reduction of HCV viral load. We suggest that the addition of statins and fibrates to antiviral regimes, especially in HCV patients with concomitant dyslipidemia, could beside the established reduction of cardiovascular risk increase the potency of antiviral therapy.Journal of Viral Hepatitis 06/2014; · 3.08 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The secretory proprotein convertases (PCs) family comprises 9 members: PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P and PCSK9. The first 7 PCs cleave their substrates at single or paired basic residues, 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.Journal of Biological Chemistry 06/2013; · 4.60 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: 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.Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 03/2014; 19(Suppl 1):S1-4.