Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A.
Numerous anti-hepatitis C virus (HCV) drugs targeting either the viral nonstructural 3 (NS3) protease or NS5B polymerase are currently in clinical testing. However, rapid resistance development is a major problem and optimal therapy will clearly require a combination of multiple mechanisms of action. Cyclosporine A (CsA) and its nonimmunosuppressant derivatives are among the more promising drugs under development. Based on work with subgenomic HCV replicons it has been thought that they act as NS5B-inhibitors. In this study we show that CsA inhibits replication of full-length HCV Japanese Fulminant Hepatitis (JFH1) genomes about 10-fold more efficiently than subgenomic replicons. This effect is dependent on the presence of NS2 in the viral polyprotein and mediated through cellular cyclophilin A. NS2 is either an additional target for CsA-dependent inhibition or modulates the antiviral activity against NS3 to NS5B proteins. CsA is thus the first anti-HCV drug shown to act through NS2.


CONCLUSIONS
CsA inhibits replication of JFH1 full-length genomes much more efficiently than subgenomic replicons by targeting cleavage at the NS2/NS3 junction and possibly other nonreplication lifecycle steps.
Ciesek
Sandra
S
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
Steinmann
Eike
E
Wedemeyer
Heiner
H
Manns
Michael P
MP
Neyts
Johann
J
Tautz
Norbert
N
Madan
Vanesa
V
Bartenschlager
Ralf
R
von Hahn
Thomas
T
Pietschmann
Thomas
T
D002478:Cells, Cultured; D021984:Cyclophilin A / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016679:Genome, Viral / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D012093:Replicon / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D004791:Enzyme Inhibitors; C097010:NS2 protein, Hepatitis C virus; D017361:Viral Nonstructural Proteins; D016572:Cyclosporine; D021984:Cyclophilin A