title: Multiple cyclophilins involved in different cellular pathways mediate HCV replication.
abstract: Three cyclophilin inhibitors (DEBIO-025, SCY635, and NIM811) are currently in clinical trials for hepatitis C therapy. The mechanism of action of these, however, is not completely understood. There are at least 16 cyclophilins expressed in human cells which are involved in a diverse set of cellular processes. Large-scale siRNA experiments, chemoproteomic assays with cyclophilin binding compounds, and mRNA profiling of HCV replicon containing cells were used to identify the cyclophilins that are instrumental to HCV replication. The previously reported cyclophilin A was confirmed and additional cyclophilin containing pathways were identified. Together, the experiments provide strong evidence that NIM811 reduces viral replication by inhibition of multiple cyclophilins and pathways with protein trafficking as the most strongly and persistently affected pathway.
authors.affiliation: Novartis Institutes of Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: L Alex
authors.initials: LA
authors.lastname: Gaither
authors.forename: Jason
authors.initials: J
authors.lastname: Borawski
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Anderson
authors.forename: Kara A
authors.initials: KA
authors.lastname: Balabanis
authors.forename: Piroska
authors.initials: P
authors.lastname: Devay
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.forename: Christina
authors.initials: C
authors.lastname: Rau
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.forename: Craig
authors.initials: C
authors.lastname: Mickanin
authors.forename: Shanchuan
authors.initials: S
authors.lastname: Zhao
authors.forename: Chad
authors.initials: C
authors.lastname: Vickers
authors.forename: Lac
authors.initials: L
authors.lastname: Lee
authors.forename: Gejing
authors.initials: G
authors.lastname: Deng
authors.forename: Jeremy
authors.initials: J
authors.lastname: Baryza
authors.forename: Roger A
authors.initials: RA
authors.lastname: Fujimoto
authors.forename: Kai
authors.initials: K
authors.lastname: Lin
authors.forename: Teresa
authors.initials: T
authors.lastname: Compton
authors.forename: Brigitte
authors.initials: B
authors.lastname: Wiedmann
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D021983:Cyclophilins / Q000378:metabolism*; D016572:Cyclosporine / Q000737:chemistry / Q000494:pharmacology; D020869:Gene Expression Profiling; D020868:Gene Silencing; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D020543:Proteome / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D020543:Proteome; D034741:RNA, Small Interfering; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D021983:Cyclophilins