title: The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction.
abstract: Alisporivir (Debio-025) is an analogue of cyclosporine A and represents the prototype of a new class of non-immunosuppressive cyclophilin inhibitors. In vitro and in vivo studies have shown that alisporivir inhibits hepatitis C virus (HCV) replication, and ongoing clinical trials are exploring its therapeutic potential in patients with chronic hepatitis C. Recent data suggest that the antiviral effect is mediated by inhibition of cyclophilin A, which is an essential host factor in the HCV life cycle. However, alisporivir also inhibits mitochondrial permeability transition by binding to cyclophilin D. Because HCV is known to affect mitochondrial function, we explored the effect of alisporivir on HCV protein-mediated mitochondrial dysfunction. Through the use of inducible cell lines, which allow to investigate the effects of HCV polyprotein expression independent from viral RNA replication and which recapitulate the major alterations of mitochondrial bioenergetics observed in infectious cell systems, we show that alisporivir prevents HCV protein-mediated decrease of cell respiration, collapse of mitochondrial membrane potential, overproduction of reactive oxygen species and mitochondrial calcium overload. Strikingly, some of the HCV-mediated mitochondrial dysfunctions could even be rescued by alisporivir.
  
  
  CONCLUSIONS
  These observations provide new insights into the pathogenesis of HCV-related liver disease and reveal an additional mechanism of action of alisporivir that is likely beneficial in the treatment of chronic hepatitis C.
authors.affiliation: Department of Biomedical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarato
authors.forename: Annamaria
authors.initials: A
authors.lastname: D'Aprile
authors.forename: Bruno
authors.initials: B
authors.lastname: Gavillet
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vuagniaux
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Capitanio
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D021983:Cyclophilins / Q000037:antagonists & inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012680:Sensitivity and Specificity; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D017382:Reactive Oxygen Species; D016572:Cyclosporine; D021983:Cyclophilins; D002118:Calcium; C499715:alisporivir