Identification of a resveratrol tetramer as a potent inhibitor of hepatitis C virus helicase

Sungjin Lee, Kee Dong Yoon, Myungeun Lee, Yoojin Cho, Gahee Choi, Hongje Jang, Beomseok Kim, Da Hee Jung, Jin Gyo Oh, Geon Woo Kim, Jong Won Oh, Yong Joo Jeong, Ho Jeong Kwon, Soo Kyung Bae, Dal Hee Min, Marc P. Windisch, Tae Hwe Heo, Choongho Lee

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background and Purpose Hepatitis C virus (HCV) infection is responsible for various chronic inflammatory liver diseases. Here, we have identified a naturally occurring compound with anti-HCV activity and have elucidated its mode of antiviral action. Experimental Approach Luciferase reporter and real-time RT-PCR assays were used to measure HCV replication. Western blot, fluorescence-labelled HCV replicons and infectious clones were employed to quantitate expression levels of viral proteins. Resistant HCV mutant mapping, in vitro NS3 protease, helicase, NS5B polymerase and drug affinity responsive target stability assays were also used to study the antiviral mechanism. Key Results A resveratrol tetramer, vitisin B from grapevine root extract showed high potency against HCV replication (EC50 = 6 nM) with relatively low cytotoxicity (EC50 >10 μM). Combined treatment of vitisin B with an NS5B polymerase inhibitor (sofosbuvir) exhibited a synergistic or at least additive antiviral activity. Analysis of a number of vitisin B-resistant HCV variants suggested an NS3 helicase as its potential target. We confirmed a direct binding between vitisin B and a purified NS3 helicase in vitro. Vitisin B was a potent inhibitor of a HCV NS3 helicase (IC50 = 3 nM). In vivo, Finally, we observed a preferred tissue distribution of vitisin B in the liver after i.p. injection in rats, at clinically attainable concentrations. Conclusion and Implications Vitisin B is one of the most potent HCV helicase inhibitors identified so far. Vitisin B is thus a prime candidate to be developed as the first HCV drug derived from natural products.

Original languageEnglish
Pages (from-to)191-211
Number of pages21
JournalBritish Journal of Pharmacology
Volume173
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1

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Hepacivirus
Antiviral Agents
Virus Replication
resveratrol
Replicon
malvidin-3-O-glucoside-4 vinyl
Viral Proteins
Virus Diseases
Tissue Distribution
Biological Products
Luciferases
Pharmaceutical Preparations
Inhibitory Concentration 50
Liver Diseases
Real-Time Polymerase Chain Reaction
Peptide Hydrolases
Clone Cells
Fluorescence
Western Blotting
Injections

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Lee, Sungjin ; Yoon, Kee Dong ; Lee, Myungeun ; Cho, Yoojin ; Choi, Gahee ; Jang, Hongje ; Kim, Beomseok ; Jung, Da Hee ; Oh, Jin Gyo ; Kim, Geon Woo ; Oh, Jong Won ; Jeong, Yong Joo ; Kwon, Ho Jeong ; Bae, Soo Kyung ; Min, Dal Hee ; Windisch, Marc P. ; Heo, Tae Hwe ; Lee, Choongho. / Identification of a resveratrol tetramer as a potent inhibitor of hepatitis C virus helicase. In: British Journal of Pharmacology. 2016 ; Vol. 173, No. 1. pp. 191-211.
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abstract = "Background and Purpose Hepatitis C virus (HCV) infection is responsible for various chronic inflammatory liver diseases. Here, we have identified a naturally occurring compound with anti-HCV activity and have elucidated its mode of antiviral action. Experimental Approach Luciferase reporter and real-time RT-PCR assays were used to measure HCV replication. Western blot, fluorescence-labelled HCV replicons and infectious clones were employed to quantitate expression levels of viral proteins. Resistant HCV mutant mapping, in vitro NS3 protease, helicase, NS5B polymerase and drug affinity responsive target stability assays were also used to study the antiviral mechanism. Key Results A resveratrol tetramer, vitisin B from grapevine root extract showed high potency against HCV replication (EC50 = 6 nM) with relatively low cytotoxicity (EC50 >10 μM). Combined treatment of vitisin B with an NS5B polymerase inhibitor (sofosbuvir) exhibited a synergistic or at least additive antiviral activity. Analysis of a number of vitisin B-resistant HCV variants suggested an NS3 helicase as its potential target. We confirmed a direct binding between vitisin B and a purified NS3 helicase in vitro. Vitisin B was a potent inhibitor of a HCV NS3 helicase (IC50 = 3 nM). In vivo, Finally, we observed a preferred tissue distribution of vitisin B in the liver after i.p. injection in rats, at clinically attainable concentrations. Conclusion and Implications Vitisin B is one of the most potent HCV helicase inhibitors identified so far. Vitisin B is thus a prime candidate to be developed as the first HCV drug derived from natural products.",
author = "Sungjin Lee and Yoon, {Kee Dong} and Myungeun Lee and Yoojin Cho and Gahee Choi and Hongje Jang and Beomseok Kim and Jung, {Da Hee} and Oh, {Jin Gyo} and Kim, {Geon Woo} and Oh, {Jong Won} and Jeong, {Yong Joo} and Kwon, {Ho Jeong} and Bae, {Soo Kyung} and Min, {Dal Hee} and Windisch, {Marc P.} and Heo, {Tae Hwe} and Choongho Lee",
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Lee, S, Yoon, KD, Lee, M, Cho, Y, Choi, G, Jang, H, Kim, B, Jung, DH, Oh, JG, Kim, GW, Oh, JW, Jeong, YJ, Kwon, HJ, Bae, SK, Min, DH, Windisch, MP, Heo, TH & Lee, C 2016, 'Identification of a resveratrol tetramer as a potent inhibitor of hepatitis C virus helicase', British Journal of Pharmacology, vol. 173, no. 1, pp. 191-211. https://doi.org/10.1111/bph.13358

Identification of a resveratrol tetramer as a potent inhibitor of hepatitis C virus helicase. / Lee, Sungjin; Yoon, Kee Dong; Lee, Myungeun; Cho, Yoojin; Choi, Gahee; Jang, Hongje; Kim, Beomseok; Jung, Da Hee; Oh, Jin Gyo; Kim, Geon Woo; Oh, Jong Won; Jeong, Yong Joo; Kwon, Ho Jeong; Bae, Soo Kyung; Min, Dal Hee; Windisch, Marc P.; Heo, Tae Hwe; Lee, Choongho.

In: British Journal of Pharmacology, Vol. 173, No. 1, 01.01.2016, p. 191-211.

Research output: Contribution to journalArticle

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T1 - Identification of a resveratrol tetramer as a potent inhibitor of hepatitis C virus helicase

AU - Lee, Sungjin

AU - Yoon, Kee Dong

AU - Lee, Myungeun

AU - Cho, Yoojin

AU - Choi, Gahee

AU - Jang, Hongje

AU - Kim, Beomseok

AU - Jung, Da Hee

AU - Oh, Jin Gyo

AU - Kim, Geon Woo

AU - Oh, Jong Won

AU - Jeong, Yong Joo

AU - Kwon, Ho Jeong

AU - Bae, Soo Kyung

AU - Min, Dal Hee

AU - Windisch, Marc P.

AU - Heo, Tae Hwe

AU - Lee, Choongho

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Background and Purpose Hepatitis C virus (HCV) infection is responsible for various chronic inflammatory liver diseases. Here, we have identified a naturally occurring compound with anti-HCV activity and have elucidated its mode of antiviral action. Experimental Approach Luciferase reporter and real-time RT-PCR assays were used to measure HCV replication. Western blot, fluorescence-labelled HCV replicons and infectious clones were employed to quantitate expression levels of viral proteins. Resistant HCV mutant mapping, in vitro NS3 protease, helicase, NS5B polymerase and drug affinity responsive target stability assays were also used to study the antiviral mechanism. Key Results A resveratrol tetramer, vitisin B from grapevine root extract showed high potency against HCV replication (EC50 = 6 nM) with relatively low cytotoxicity (EC50 >10 μM). Combined treatment of vitisin B with an NS5B polymerase inhibitor (sofosbuvir) exhibited a synergistic or at least additive antiviral activity. Analysis of a number of vitisin B-resistant HCV variants suggested an NS3 helicase as its potential target. We confirmed a direct binding between vitisin B and a purified NS3 helicase in vitro. Vitisin B was a potent inhibitor of a HCV NS3 helicase (IC50 = 3 nM). In vivo, Finally, we observed a preferred tissue distribution of vitisin B in the liver after i.p. injection in rats, at clinically attainable concentrations. Conclusion and Implications Vitisin B is one of the most potent HCV helicase inhibitors identified so far. Vitisin B is thus a prime candidate to be developed as the first HCV drug derived from natural products.

AB - Background and Purpose Hepatitis C virus (HCV) infection is responsible for various chronic inflammatory liver diseases. Here, we have identified a naturally occurring compound with anti-HCV activity and have elucidated its mode of antiviral action. Experimental Approach Luciferase reporter and real-time RT-PCR assays were used to measure HCV replication. Western blot, fluorescence-labelled HCV replicons and infectious clones were employed to quantitate expression levels of viral proteins. Resistant HCV mutant mapping, in vitro NS3 protease, helicase, NS5B polymerase and drug affinity responsive target stability assays were also used to study the antiviral mechanism. Key Results A resveratrol tetramer, vitisin B from grapevine root extract showed high potency against HCV replication (EC50 = 6 nM) with relatively low cytotoxicity (EC50 >10 μM). Combined treatment of vitisin B with an NS5B polymerase inhibitor (sofosbuvir) exhibited a synergistic or at least additive antiviral activity. Analysis of a number of vitisin B-resistant HCV variants suggested an NS3 helicase as its potential target. We confirmed a direct binding between vitisin B and a purified NS3 helicase in vitro. Vitisin B was a potent inhibitor of a HCV NS3 helicase (IC50 = 3 nM). In vivo, Finally, we observed a preferred tissue distribution of vitisin B in the liver after i.p. injection in rats, at clinically attainable concentrations. Conclusion and Implications Vitisin B is one of the most potent HCV helicase inhibitors identified so far. Vitisin B is thus a prime candidate to be developed as the first HCV drug derived from natural products.

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