Cyclophilin Inhibitors: An Emerging Class of Therapeutics for the Treatment of Chronic Hepatitis C Infection

Abstract

The advent of the replicon system together with advances in cell culture have contributed significantly to our understanding of the function of virally-encoded structural and nonstructural proteins in the replication cycle of the hepatitis C virus. In addition, in vitro systems have been used to identify several host proteins whose expression is critical for supporting such diverse activities as viral entry, RNA replication, particle assembly, and the release of infectious virions. Among all known host proteins that participate in the HCV replication cycle, cyclophilins are unique because they constitute the only host target that has formed the basis of pharmaceutical drug discovery and drug development programs. The introduction of the nonimmunosuppressive cyclophilin inhibitors into clinical testing has confirmed the clinical utility of CsA-based inhibitors for the treatment of individuals with chronic hepatitis C infection and has yielded new insights into their mechanism(s) of action. This review describes the biochemical evidence for the potential roles played by cyclophilins in supporting HCV RNA replication and summarizes clinical trial results obtained with the first generation of nonimmunosuppressive cyclophilin inhibitors.

Insights into peptidyl-prolyl cis–trans isomerase structure and function in immunocytes

“…SCY-635 and Alisporivir together with NIM811 are now considered as the most advanced of all host-targeted antiviral agents [56][57][58]. A great deal of work describing the results of clinical trial using nonimmunosuppressive NIM811, SCY-635 and Alisporivir against HCV infection and anti viral effects of other CsA derivatives has recently been summarized elsewhere [59,60].…”

Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds

“…Compound 33 was recently found effective in a phase 2 clinical trial in patients given interferon combination therapy but ultimately discontinued due to weaker antiviral activity when compared to alisporivir. 137 Alisporivir ( 34 ) is a nonimmunosuppressive 32 derivative that is semisynthetically modified with an N -methylalanine substitution at position 3 and N -ethylvaline replacement at position 4. 138 Alisporivir potently inhibits HCV replication and was shown to be effective in patients co-infected by HIV and HCV.…”

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

“…Cyclosporine FR901459 was nearly 20-fold more potent than CsA but 4-fold less potent than CsH for inhibiting the FPR1-dependent response [32]. Extensive chemical modification of the cyclosporine scaffold led to the discovery of various non-immunosuppressive cyclophilin inhibitors for the treatment of hepatitis C infection and other diseases [33, 34]. However, the effects of these synthetic cyclosporine analogs on FPR functions have not been reported.…”