Cyclophilin Inhibitors

Abstract

The percentage of patients chronically infected with hepatitis C virus (HCV) who have reached sustained antiviral response has increased since the introduction of the pegylated interferon-alpha (pIFNa) and ribavirin (RBV) treatment. However, the current standard pIFNa/RBV therapy not only has a low success rate (about 50%) but is often associated with serious side effects. Thus, there is an urgent need for the development of new anti-HCV agents. Cyclophilin (Cyp) inhibitors are among the most promising of the new anti-HCV agents under development. Recent clinical studies demonstrate that Cyp inhibitors are potent anti-HCV drugs, with a novel mechanism of action and efficacy profiles that make them attractive candidates for combination with current and future HCV treatments.

Early events in the generation of autophagosomes are required for the formation of membrane structures involved in hepatitis C virus genome replication

“…2a), confirming the requirement for these two proteins in HCV genomic replication. As positive controls, the SGR-Feo-JFH-1-harbouring cells were treated with two well-characterized inhibitors of HCV genome replication, either cyclosporin A (CsA) (Gallay, 2009) or DCV. Both inhibitors effectively blocked HCV RNA replication as judged by reductions in both luciferase and NS5A expression (lanes 5 and 6 in Fig.…”

Cyclophilin A-independent recruitment of NS5A and NS5B into hepatitis C virus replication complexes

“…There is a growing body of evidence that cyclosporine A (CsA) and CsA analogues exert their potent anti-hepatitis C virus (HCV) effect both in vitro (Coelmont et al, 2009;Fernandes et al, 2007;Goto et al, 2006;Ma et al, 2006;Mathy et al, 2008;Paeshuyse et al, 2006;Robida et al, 2007) and in vivo (Flisiak et al, 2008(Flisiak et al, , 2009Hopkins et al, 2009) by neutralizing the enzymic activity of cyclophilins (Cyp) (Chatterji et al, 2009;Gallay, 2009;Goto et al, 2009;Ishii et al, 2006;Kaul et al, 2009;Liu et al, 2009;Nakagawa et al, 2004;Watashi et al, 2003Watashi et al, , 2005Yang et al, 2008). Supporting this notion, several studies including ours showed that stable knockdown of cyclophilin A (CypA) expression in Huh-7 cells decreases HCV replication (Chatterji et al, 2010;Kaul et al, 2009;Yang et al, 2008), suggesting that CypA is the main member of the Cyp family that assists HCV replication.…”

“…However, the mechanisms by which CypA enhances HCV replication remain to be fully elucidated. To date, no less than four distinct models have been proposed for the role of CypA in the HCV life cycle (Gallay, 2009). …”

Cyclosporines: Biosynthesis and Beyond

“…[MeIle 4 ] CsA was the first cyclosporine analog reported that lacked immunosuppressive activity while maintaining strong cyclophilin binding and peptidyl-prolyl-cis/transisomerase inhibiting activity [113]. It shows strong anti-immunodeficiency virus type 1 activity [118], antimalarial activity [119], and anti-hepatitis C activity [120,121]. Furthermore, [MeIle 4 ] CsA and its homologues proved valuable research tools for the discrimination between the effects of CsA on calcineurin and on cyclophilin (e.g., [122][123][124]).…”