Multiple effects of silymarin on the hepatitis C virus lifecycle.
Silymarin, an extract from milk thistle (Silybum marianum), and its purified flavonolignans have been recently shown to inhibit hepatitis C virus (HCV) infection, both in vitro and in vivo. In the current study, we further characterized silymarin's antiviral actions. Silymarin had antiviral effects against hepatitis C virus cell culture (HCVcc) infection that included inhibition of virus entry, RNA and protein expression, and infectious virus production. Silymarin did not block HCVcc binding to cells but inhibited the entry of several viral pseudoparticles (pp), and fusion of HCVpp with liposomes. Silymarin but not silibinin inhibited genotype 2a NS5B RNA-dependent RNA polymerase (RdRp) activity at concentrations 5 to 10 times higher than required for anti-HCVcc effects. Furthermore, silymarin had inefficient activity on the genotype 1b BK and four 1b RDRPs derived from HCV-infected patients. Moreover, silymarin did not inhibit HCV replication in five independent genotype 1a, 1b, and 2a replicon cell lines that did not produce infectious virus. Silymarin inhibited microsomal triglyceride transfer protein activity, apolipoprotein B secretion, and infectious virion production into culture supernatants. Silymarin also blocked cell-to-cell spread of virus.


CONCLUSIONS
Although inhibition of in vitro NS5B polymerase activity is demonstrable, the mechanisms of silymarin's antiviral action appear to include blocking of virus entry and transmission, possibly by targeting the host cell.
Department of Laboratory Medicine, University of Washington, Seattle, WA 98104-2499, USA.
Jessica
J
Wagoner
Amina
A
Negash
Olivia J
OJ
Kane
Laura E
LE
Martinez
Yaakov
Y
Nahmias
Nigel
N
Bourne
David M
DM
Owen
Joe
J
Grove
Claire
C
Brimacombe
Jane A
JA
McKeating
Eve-Isabelle
EI
Pécheur
Tyler N
TN
Graf
Nicholas H
NH
Oberlies
Volker
V
Lohmann
Feng
F
Cao
John E
JE
Tavis
Stephen J
SJ
Polyak
D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D012838:Silymarin / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D053586:Virus Internalization / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D012838:Silymarin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase