Titre
The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Quarato, G.
Auteure/Auteur
D'Aprile, A.
Auteure/Auteur
Gavillet, B.
Auteure/Auteur
Vuagniaux, G.
Auteure/Auteur
Moradpour, D.
Auteure/Auteur
Capitanio, N.
Auteure/Auteur
Piccoli, C.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1527-3350
Statut éditorial
Publié
Date de publication
2012
Volume
55
Numéro
5
Première page
1333
Dernière page/numéro d’article
1343
Langue
anglais
Notes
Publication types: Journal ArticlePublication Status: ppublish
Résumé
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. Conclusion: 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. (HEPATOLOGY 2012).
PID Serval
serval:BIB_A39F43707B2D
PMID
Open Access
Oui
Date de création
2012-05-19T17:41:32.140Z
Date de création dans IRIS
2025-05-21T02:15:01Z