Background: Silymarin extracted from milk thistle fruit (Cardui fructus) has been used as a hepatoprotective
drug since ancient times. A few years ago first data emerged suggesting antiviral
activity against hepatitis C virus (HCV) for silibinin, a silymarin component. The
mechanisms by which HCV suppression occurs have not been fully characterized yet.
A substantial amount of data has been produced leading to different hypotheses how
silibinin interacts with the HCV reproductive cycle.
Inhibition of RNA polymerase (NS5B): Previously it has been shown by different independent investigators that silymarin-derived
compounds like silibinin can inhibit HCV RdRp activity in in-vitro assays with recombinant
HCV non-structural 5B (NS5B) protein suggesting that silibinin may differentially
modulate RNA polymerase of different HCV genotypes.
Inhibition of viral entry: Other authors more recently presented data indicating that silibinin might inhibit
HCV entry at the fusion stage with the host cell membrane, by inhibiting key steps
in the clathrin-dependent entry of HCV into hepatocytes.
Interaction with NS4B: Last year virologists from Heidelberg identified a mutation in non-structural 4B
(NS4B) protein conferring silibinin resistance to HCV genotype 1b in the replicon
model. They concluded that silibinin might alter the membranous web morphology by
interfering with the non-structural 3 and 4B (NS3/4B) protein interaction which is
essential for the viral reproduction cycle.
Modelling the infection: Specialists from Los Alamos National Laboratory analysed HCV RNA kinetics from patients
infected with HCV to resolve the controversy whether silibinin inhibits intracellular
HCV reproduction or whether it blocks other phases of the HCV lifecycle such as virus
entry or release. They showed a bi-phase decline in viral RNA which might be a hint
for a pleiotropic mechanism of silibinin with both a fast direct antiviral effect
on the reproduction complex and a slower impact on cell infection by affecting entry
or release.
