title: Inhibition of hepatitis C virus replication by Monascus pigment derivatives that interfere with viral RNA polymerase activity and the mevalonate biosynthesis pathway.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Biotechnology,  Yonsei University, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-749,  Korea.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Sun
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Kim
authors.forename: Geon-Woo
authors.initials: GW
authors.lastname: Kim
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Rhee
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Heeyong
authors.initials: H
authors.lastname: Jung
authors.forename: Jungae
authors.initials: J
authors.lastname: Jeun
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Han
authors.forename: Chul Soo
authors.initials: CS
authors.lastname: Shin
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Oh
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001665:Binding Sites; D053898:Biosynthetic Pathways / Q000235:genetics; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D032741:Monascus / Q000737:chemistry*; D010860:Pigments, Biological / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D010860:Pigments, Biological; D012321:DNA-Directed RNA Polymerases; D008798:Mevalonic Acid
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2561-6
references.pmid: 15699349
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15865-70
references.pmid: 14668447
references.citation: Drugs. 2010;70(2):147-65
references.pmid: 20108989
references.citation: Nat Med. 2005 Jul;11(7):791-6
references.pmid: 15951748
references.citation: J Biol Chem. 2003 Mar 14;278(11):9489-95
references.pmid: 12509436
references.citation: J Antibiot (Tokyo). 2009 Jan;62(1):5-16
references.pmid: 19132062
references.citation: Bioorg Med Chem Lett. 2006 Nov 15;16(22):5888-91
references.pmid: 16934455
references.citation: Expert Opin Investig Drugs. 2010 Aug;19(8):963-75
references.pmid: 20629614
references.citation: Expert Opin Investig Drugs. 2009 Jun;18(6):709-25
references.pmid: 19426125
references.citation: J Biol Chem. 2004 Nov 26;279(48):50031-41
references.pmid: 15364941
references.citation: J Biol Chem. 2005 May 6;280(18):18202-10
references.pmid: 15746101
references.citation: Org Lett. 2005 Nov 24;7(24):5521-4
references.pmid: 16288546
references.citation: Biochem J. 2001 Jan 1;353(Pt 1):59-67
references.pmid: 11115399
references.citation: J Viral Hepat. 2009 Oct;16(10):697-704
references.pmid: 19243496
references.citation: Mol Cell. 2005 May 13;18(4):425-34
references.pmid: 15893726
references.citation: Oncology. 1994 Jan-Feb;51(1):108-12
references.pmid: 8265094
references.citation: Adv Food Nutr Res. 2007;53:123-59
references.pmid: 17900498
references.citation: Antimicrob Agents Chemother. 2008 Oct;52(10):3523-31
references.pmid: 18694956
references.citation: J Agric Food Chem. 2003 Feb 26;51(5):1302-6
references.pmid: 12590473
references.citation: Can J Microbiol. 1977 Oct;23(10):1360-72
references.pmid: 21736
references.citation: J Biol Chem. 2006 Apr 14;281(15):9833-6
references.pmid: 16407182
references.citation: Hepatology. 2006 Jul;44(1):117-25
references.pmid: 16799963
references.citation: FEMS Microbiol Lett. 2006 Nov;264(1):117-24
references.pmid: 17020557
references.citation: J Hepatol. 2009 Jul;51(1):39-46
references.pmid: 19446909
references.citation: Antiviral Res. 2011 Jul;91(1):1-10
references.pmid: 21549154
references.citation: Nat Cell Biol. 2007 Sep;9(9):1089-97
references.pmid: 17721513
references.citation: Cancer Lett. 2009 Jul 8;279(2):230-7
references.pmid: 19264393
references.citation: RNA Biol. 2011 Mar-Apr;8(2):258-69
references.pmid: 21593584
references.citation: Virology. 2004 Jul 1;324(2):450-61
references.pmid: 15207630
references.citation: World J Gastroenterol. 2007 Nov 21;13(43):5673-81
references.pmid: 17963291
references.citation: J Virol. 2006 Jun;80(12):6146-54
references.pmid: 16731953
references.citation: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13034-9
references.pmid: 10557268
references.citation: Appl Microbiol Biotechnol. 2006 May;70(5):533-40
references.pmid: 16283302
references.citation: Nature. 1990 Feb 1;343(6257):425-30
references.pmid: 1967820
references.citation: Nature. 2005 Aug 18;436(7053):973-8
references.pmid: 16107838
references.citation: J Virol. 2007 Jul;81(13):6909-19
references.pmid: 17459932
references.citation: Klin Wochenschr. 1988 May 16;66(10):421-7
references.pmid: 3294493
references.citation: PLoS Pathog. 2007 Aug 31;3(8):e108
references.pmid: 17784784
references.citation: J Virol. 2005 Feb;79(3):1623-34
references.pmid: 15650188
references.citation: Colloids Surf B Biointerfaces. 2006 Feb 1;47(2):153-9
references.pmid: 16423514