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Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A
Author(s) -
Ciesek Sandra,
Steinmann Eike,
Wedemeyer Heiner,
Manns Michael P.,
Neyts Johann,
Tautz Norbert,
Madan Vanesa,
Bartenschlager Ralf,
von Hahn Thomas,
Pietschmann Thomas
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23281
Subject(s) - virology , cyclophilin , cyclophilin a , hepatitis c virus , hepatitis a virus , virus , biology , microbiology and biotechnology , biochemistry , gene
Abstract 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. Conclusion: 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. (H EPATOLOGY 2009.)