Milk Thistle Silibinin Extracts Inhibit HCV Polymerase in Laboratory Study

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Milk Thistle Silibinin Extracts Inhibit HCV Polymerase in Laboratory Study

SUMMARY: Silibinin and related biologically active compounds from the milk thistle plant demonstrated direct inhibition of hepatitis C virus (HCV) polymerase in laboratory cell culture experiments, according to a report published in the March 2010 issue of Gastroenterology. It did not, however, act as an HCV protease inhibitor.

The milk thistle plant, Silybum marianum, is widely used in traditional herbal medicine as a treatment for liver disease. While milk thistle and its components are most often studied as a potential anti-fibrosis or liver-protective therapy, it may also have direct activity against HCV.

Abdelhakim Ahmed-Belkacem and colleagues from France and Germany used different laboratory models to evaluate whether active compounds in silymarin could inhibit the function of HCV enzymes, similar to the effects of the novel directly-targeting antiviral therapies now making their way through the development pipeline.Silymarin is a mixture of several milk thistle "flavonolignans" (a type of plant component) including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin, the study authors noted as background. Past research has shown that silibin inhibits HCV replication in laboratory replicons, and intravenous infusion leads to dose-dependent reduction in HCV RNA viral load in patients.The researchers tested the inhibitory activity of silymarin components against the HCV RNA-dependent RNA polymerase and NS3/4A protease enzymes, which play crucial roles in viral

replication. They looked at the compounds' ability to interfere with HCV enzyme activity, and to inhibit replication in an HCV genotype 1b replicon model and a genotype 2a JFH1 infectious HCV cell culture model.esults

Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms, and Legalon SIL -- a commercially available intravenous silibinin preparation -- all inhibited HCV polymerase function.

50% inhibitory concentrations (IC50) were around 75-100 muM.

None of these compounds inhibited HCV protease function.

Silibinin A and silibinin B inhibited HCV replication in both the genotype 1b replicon and in the JFH1 cell culture model.

"Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture," the study authors concluded. "This effect is at least partly explained by the ability of these compounds to inhibit HCV RNA-dependent RNA polymerase activity.""Our results provide a basis for the optimization and subsequent development of members of the flavonoid family as specific HCV antivirals," they added.Research Team "Pathophysiology and Therapy of Chronic Viral Hepatitis," INSERM U955, Créteil, France; Institut de Biologie de Lille (CNRS UMR8161), Université de Lille I and II and Institut Pasteur de Lille, Lille, France; Department of Virology, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; Rottapharm/Madaus, Cologne, Germany; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université

Paris 12, Créteil, France.4/6/10

ReferenceA Ahmed-Belkacem, N Ahnou, L Barbotte, and others. Silibinin and Related Compounds are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase. Gastroenterology 138(3): 1112-1122 (Abstract). March 2010.

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