Inhibition of hepatitis C virus replication by Monascus pigment derivatives that interfere with viral RNA polymerase activity and the mevalonate biosynthesis pathway

Ji Min Sun, Seong Jun Kim, Geon Woo Kim, Jin Kyu Rhee, Nam Doo Kim, Heeyong Jung, Jungae Jeun, Seung Hoon Lee, Seung Hyun Han, Chul Soo Shin, Jong-Won Oh

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Objectives: Hepatitis C virus (HCV) infection causes chronic liver disease and is a major public health problem worldwide. The aim of this study was to evaluate the potential of Monascus pigment derivatives, which were derived from a microbial secondary metabolite synthesized from polyketides by Monascus spp., as HCV antiviral agents. Methods: We performed an in vitro RNA-dependent RNA polymerase (RdRp) assay to screen for HCV RdRp inhibitors. The anti-HCV activity of RdRp inhibitors in HCV-replicating cells was evaluated by quantification of the RNA viral genome. Molecular docking analysis was performed to predict the binding sites of the selected RdRp inhibitors. Results: We have identified a Monascus pigment and its derivatives as inhibitors of the HCV NS5B RdRp. A group of Monascus orange pigment (MOP) amino acid derivatives, in which the reactive oxygen moiety was changed to amino acids, significantly inhibited HCV replication. Further, combination of the MOP derivatives (Phe, Val or Leu conjugates) with interferon (IFN)-α inhibited HCV replication more than IFN-α treatment alone. Lastly, molecular docking studies indicate the inhibitors may bind to a thumb subdomain allosteric site of NS5B. The antiviral activity of the MOP derivatives was related to a modulation of the mevalonate pathway, since the mevalonate-induced increase in HCV replication was suppressed by the MOP compounds. Conclusions: Our results identify amino acid derivatives of MOP as potential anti-HCV agents and suggest that their combination with IFN-α might offer an alternative strategy for the control of HCV replication.

Original languageEnglish
Pages (from-to)49-58
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Volume67
Issue number1
DOIs
Publication statusPublished - 2012 Nov 21

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Monascus
Mevalonic Acid
Viral RNA
DNA-Directed RNA Polymerases
Virus Replication
Hepacivirus
RNA Replicase
Interferons
Amino Acids
Antiviral Agents
Molecular Docking Simulation
Allosteric Site
Polyketides
Viral Genome
Thumb
Virus Diseases
Liver Diseases

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Sun, Ji Min ; Kim, Seong Jun ; Kim, Geon Woo ; Rhee, Jin Kyu ; Kim, Nam Doo ; Jung, Heeyong ; Jeun, Jungae ; Lee, Seung Hoon ; Han, Seung Hyun ; Shin, Chul Soo ; Oh, Jong-Won. / Inhibition of hepatitis C virus replication by Monascus pigment derivatives that interfere with viral RNA polymerase activity and the mevalonate biosynthesis pathway. In: Journal of Antimicrobial Chemotherapy. 2012 ; Vol. 67, No. 1. pp. 49-58.
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abstract = "Objectives: Hepatitis C virus (HCV) infection causes chronic liver disease and is a major public health problem worldwide. The aim of this study was to evaluate the potential of Monascus pigment derivatives, which were derived from a microbial secondary metabolite synthesized from polyketides by Monascus spp., as HCV antiviral agents. Methods: We performed an in vitro RNA-dependent RNA polymerase (RdRp) assay to screen for HCV RdRp inhibitors. The anti-HCV activity of RdRp inhibitors in HCV-replicating cells was evaluated by quantification of the RNA viral genome. Molecular docking analysis was performed to predict the binding sites of the selected RdRp inhibitors. Results: We have identified a Monascus pigment and its derivatives as inhibitors of the HCV NS5B RdRp. A group of Monascus orange pigment (MOP) amino acid derivatives, in which the reactive oxygen moiety was changed to amino acids, significantly inhibited HCV replication. Further, combination of the MOP derivatives (Phe, Val or Leu conjugates) with interferon (IFN)-α inhibited HCV replication more than IFN-α treatment alone. Lastly, molecular docking studies indicate the inhibitors may bind to a thumb subdomain allosteric site of NS5B. The antiviral activity of the MOP derivatives was related to a modulation of the mevalonate pathway, since the mevalonate-induced increase in HCV replication was suppressed by the MOP compounds. Conclusions: Our results identify amino acid derivatives of MOP as potential anti-HCV agents and suggest that their combination with IFN-α might offer an alternative strategy for the control of HCV replication.",
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Inhibition of hepatitis C virus replication by Monascus pigment derivatives that interfere with viral RNA polymerase activity and the mevalonate biosynthesis pathway. / Sun, Ji Min; Kim, Seong Jun; Kim, Geon Woo; Rhee, Jin Kyu; Kim, Nam Doo; Jung, Heeyong; Jeun, Jungae; Lee, Seung Hoon; Han, Seung Hyun; Shin, Chul Soo; Oh, Jong-Won.

In: Journal of Antimicrobial Chemotherapy, Vol. 67, No. 1, 21.11.2012, p. 49-58.

Research output: Contribution to journalArticle

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T1 - Inhibition of hepatitis C virus replication by Monascus pigment derivatives that interfere with viral RNA polymerase activity and the mevalonate biosynthesis pathway

AU - Sun, Ji Min

AU - Kim, Seong Jun

AU - Kim, Geon Woo

AU - Rhee, Jin Kyu

AU - Kim, Nam Doo

AU - Jung, Heeyong

AU - Jeun, Jungae

AU - Lee, Seung Hoon

AU - Han, Seung Hyun

AU - Shin, Chul Soo

AU - Oh, Jong-Won

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N2 - Objectives: Hepatitis C virus (HCV) infection causes chronic liver disease and is a major public health problem worldwide. The aim of this study was to evaluate the potential of Monascus pigment derivatives, which were derived from a microbial secondary metabolite synthesized from polyketides by Monascus spp., as HCV antiviral agents. Methods: We performed an in vitro RNA-dependent RNA polymerase (RdRp) assay to screen for HCV RdRp inhibitors. The anti-HCV activity of RdRp inhibitors in HCV-replicating cells was evaluated by quantification of the RNA viral genome. Molecular docking analysis was performed to predict the binding sites of the selected RdRp inhibitors. Results: We have identified a Monascus pigment and its derivatives as inhibitors of the HCV NS5B RdRp. A group of Monascus orange pigment (MOP) amino acid derivatives, in which the reactive oxygen moiety was changed to amino acids, significantly inhibited HCV replication. Further, combination of the MOP derivatives (Phe, Val or Leu conjugates) with interferon (IFN)-α inhibited HCV replication more than IFN-α treatment alone. Lastly, molecular docking studies indicate the inhibitors may bind to a thumb subdomain allosteric site of NS5B. The antiviral activity of the MOP derivatives was related to a modulation of the mevalonate pathway, since the mevalonate-induced increase in HCV replication was suppressed by the MOP compounds. Conclusions: Our results identify amino acid derivatives of MOP as potential anti-HCV agents and suggest that their combination with IFN-α might offer an alternative strategy for the control of HCV replication.

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