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Volume 11
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10.3390/v11100890
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Article

Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor

by
Sungjin Lee
1,
Karabasappa Mailar
1,
Mi Il Kim
1,
Minkyung Park
1,
Jiseon Kim
2,
Dal-Hee Min
3,
Tae-Hwe Heo
2,
Soo Kyung Bae
2,
Wonjun Choi
1,* and
Choongho Lee
1,*
1
College of Pharmacy, Dongguk University, Goyang 10326, Korea
2
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon 14662, Korea
3
Department of Chemistry, Seoul National University, Seoul 08826, Korea
*
Authors to whom correspondence should be addressed.
Viruses 2019, 11(10), 890; https://doi.org/10.3390/v11100890
Submission received: 6 August 2019 / Revised: 3 September 2019 / Accepted: 20 September 2019 / Published: 23 September 2019
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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Abstract

Oligostilbenoid compounds, a group of resveratrol multimers, display several anti-microbial activities through the neutralization of cytotoxic oxidants, and by inhibiting essential host and viral enzymes. In our previous study, we identified a series of oligostilbenoid compounds as potent hepatitis C virus (HCV) replication inhibitors. In particular, vitisin B, a resveratrol tetramer, exhibited the most dramatic anti-HCV activity (EC50 = 6 nM and CC50 > 10 μM) via the disruption of the viral helicase NS3 (IC50 = 3 nM). However, its further development as an HCV drug candidate was halted due to its intrinsic drawbacks, such as poor stability, low water solubility, and restricted in vivo absorption. In order to overcome these limitations, we focused on (+)-ε-viniferin, a resveratrol dimer, as an alternative. We prepared three different versions of (+)-ε-viniferin, including one which was extracted from the grapevine root (EVF) and two which were chemically synthesized with either penta-acetylation (SVF-5Ac) or no acetylation (SVF) using a newly established synthesis method. We confirmed their anti-HCV replication activities and minimal cytotoxicity by using genotype 1b and 2a HCV replicon cells. Their anti-HCV replication action also translated into a significant reduction of viral protein expression. Anti-HCV NS3 helicase activity by EVF was also verified in vitro. Finally, we demonstrated that SVF has improved pharmacokinetic properties over vitisin B. Overall, the favorable antiviral and pharmacokinetic properties of these three versions of viniferin warrant their further study as members of a promising new class of anti-HCV therapeutics.
Keywords: hepatitis C virus (HCV); viniferin; antiviral activity; NS3 helicase inhibitor; pharmacokinetics hepatitis C virus (HCV); viniferin; antiviral activity; NS3 helicase inhibitor; pharmacokinetics
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MDPI and ACS Style

Lee, S.; Mailar, K.; Kim, M.I.; Park, M.; Kim, J.; Min, D.-H.; Heo, T.-H.; Bae, S.K.; Choi, W.; Lee, C. Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor. Viruses 2019, 11, 890. https://doi.org/10.3390/v11100890

AMA Style

Lee S, Mailar K, Kim MI, Park M, Kim J, Min D-H, Heo T-H, Bae SK, Choi W, Lee C. Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor. Viruses. 2019; 11(10):890. https://doi.org/10.3390/v11100890

Chicago/Turabian Style

Lee, Sungjin, Karabasappa Mailar, Mi Il Kim, Minkyung Park, Jiseon Kim, Dal-Hee Min, Tae-Hwe Heo, Soo Kyung Bae, Wonjun Choi, and Choongho Lee. 2019. "Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor" Viruses 11, no. 10: 890. https://doi.org/10.3390/v11100890

APA Style

Lee, S., Mailar, K., Kim, M. I., Park, M., Kim, J., Min, D.-H., Heo, T.-H., Bae, S. K., Choi, W., & Lee, C. (2019). Plant-Derived Purification, Chemical Synthesis, and In Vitro/In Vivo Evaluation of a Resveratrol Dimer, Viniferin, as an HCV Replication Inhibitor. Viruses, 11(10), 890. https://doi.org/10.3390/v11100890

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