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Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
Gastroenterology. 2010 Mar; 138(3):1112-22.G

Abstract

BACKGROUND & AIMS

Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. The aim of this study was to test the principal isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models.

METHODS

The inhibitory activity of silymarin components was tested in HCV RNA-dependent RNA polymerase and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied.

RESULTS

Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL, a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% of the order of 75-100 microM. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. None of these compounds inhibited HCV protease function.

CONCLUSIONS

Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture. 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.

Authors+Show Affiliations

Research Team Pathophysiology and Therapy of Chronic Viral Hepatitis, INSERM U955, Créteil, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19962982

Citation

Ahmed-Belkacem, Abdelhakim, et al. "Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-dependent RNA Polymerase." Gastroenterology, vol. 138, no. 3, 2010, pp. 1112-22.
Ahmed-Belkacem A, Ahnou N, Barbotte L, et al. Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Gastroenterology. 2010;138(3):1112-22.
Ahmed-Belkacem, A., Ahnou, N., Barbotte, L., Wychowski, C., Pallier, C., Brillet, R., Pohl, R. T., & Pawlotsky, J. M. (2010). Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. Gastroenterology, 138(3), 1112-22. https://doi.org/10.1053/j.gastro.2009.11.053
Ahmed-Belkacem A, et al. Silibinin and Related Compounds Are Direct Inhibitors of Hepatitis C Virus RNA-dependent RNA Polymerase. Gastroenterology. 2010;138(3):1112-22. PubMed PMID: 19962982.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Silibinin and related compounds are direct inhibitors of hepatitis C virus RNA-dependent RNA polymerase. AU - Ahmed-Belkacem,Abdelhakim, AU - Ahnou,Nazim, AU - Barbotte,Laetitia, AU - Wychowski,Czeslaw, AU - Pallier,Coralie, AU - Brillet,Rozenn, AU - Pohl,Ralf-Torsten, AU - Pawlotsky,Jean-Michel, Y1 - 2009/12/04/ PY - 2009/02/20/received PY - 2009/10/30/revised PY - 2009/11/30/accepted PY - 2009/12/8/entrez PY - 2009/12/8/pubmed PY - 2010/3/26/medline SP - 1112 EP - 22 JF - Gastroenterology JO - Gastroenterology VL - 138 IS - 3 N2 - BACKGROUND & AIMS: Silymarin is a mixture of flavonolignans extracted from the milk thistle. Silymarin contains several molecules, including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin. Intravenous infusion of silibinin induces dose-dependent reduction of hepatitis C virus (HCV) RNA levels. The aim of this study was to test the principal isomers contained in silymarin preparations for their ability to inhibit HCV enzymatic functions and replication in different models. METHODS: The inhibitory activity of silymarin components was tested in HCV RNA-dependent RNA polymerase and NS3/4A protease enzyme assays. Their ability to inhibit replication of an HCV genotype 1b replicon model and the JFH1 infectious HCV model in cell culture was also studied. RESULTS: Silibinin A, silibinin B, their water-soluble dihydrogen succinate forms and Legalon SIL, a commercially available intravenous preparation of silibinin, inhibited HCV RNA-dependent RNA polymerase function, with inhibitory concentrations 50% of the order of 75-100 microM. Silibinin A and silibinin B also inhibited HCV genotype 1b replicon replication and HCV genotype 2a strain JFH1 replication in cell culture. None of these compounds inhibited HCV protease function. CONCLUSIONS: Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture. 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. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/19962982/Silibinin_and_related_compounds_are_direct_inhibitors_of_hepatitis_C_virus_RNA_dependent_RNA_polymerase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(09)02105-2 DB - PRIME DP - Unbound Medicine ER -