title: Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.
abstract: During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.
authors.affiliation: Biology Department, Gilead Sciences, Foster City, California, United States of America.
authors.forename: Rudolf K F
authors.initials: RK
authors.lastname: Beran
authors.forename: Ruchi
authors.initials: R
authors.lastname: Sharma
authors.forename: Amoreena C
authors.initials: AC
authors.lastname: Corsa
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.forename: Justin
authors.initials: J
authors.lastname: Golde
authors.forename: Greta
authors.initials: G
authors.lastname: Lundgaard
authors.forename: William E
authors.initials: WE
authors.lastname: Delaney
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Greenstein
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D021983:Cyclophilins