Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking

Abstract

SummaryHepatitis C virus (HCV) is a global health concern infecting 170 million people worldwide. Previous studies indicate that the extract from milk thistle known as silymarin and its main component silibinin inhibit HCV infection. Here we investigated the mechanism of anti-HCV action of silymarin-derived compounds at the molecular level. By using live-cell confocal imaging, single particle tracking, transmission electron microscopy and biochemical approaches on HCVinfected human hepatoma cells and primary hepatocytes, we show that silibinin potently inhibits HCV infection and hinders HCV entry by slowing down trafficking through clathrin-coated pits and vesicles. Detailed analyses revealed that silibinin altered the formation of both clathrincoated pits and vesicles in cells and caused abnormal uptake and trafficking of transferrin, a well-known cargo of the clathrin endocytic pathway. Silibinin also inhibited infection by other viruses that enter cells by clathrin-mediated endocytosis including reovirus, vesicular stomatitis and influenza viruses. Our study demonstrates that silibinin inhibits HCV early steps of infection by affecting endosomal trafficking of virions. It provides new insights into the molecular mechanisms of action of silibinin against HCV entry and also suggests that silibinin is a potential broadspectrum antiviral therapy.

Highly bioavailable silibinin nanoparticles inhibit HCV infection

“…Previous studies have shown that silibinin may also slow down clathrin-mediated endocytosis36 as well as inhibit viral membrane fusion 11. In our hands, we observed little impact from SB-DMSO and SB-NP against the HCV entry/fusion step with a luciferase reporter-tagged HCVcc.…”

Severity of Liver Disease Affects HCV Kinetics in Patients Treated with Intravenous Silibinin Monotherapy

“…Administration of SIL during the anhepatic phase and immediately after reperfusion might further prevent viral infection of the graft by blocking HCV entry [30]. Very recently, IFN-free treatment with SIL+ribavirin with on treatment mathematical modeling of viral kinetics for individualized duration of therapy was recently performed in a non-cirrhotic previous non-responder to pegylated-IFN and ribavirin.…”

Effects and Tolerance of Silymarin (Milk Thistle) in Chronic Hepatitis C Virus Infection Patients: A Meta-Analysis of Randomized Controlled Trials

“…Previous studies observed that the main active mechanisms of silymarin involve inhibiting HCV entry and fusion, promoting HCV-induced oxidative stress, precluding HCV transmission, and blocking viral production [6, 35–38]. In our meta-analysis, a trend of beneficial effect on serum HCV RNA of silymarin was observed when both oral and intravenous silymarin were evaluated, although no significance was found.…”