Cyclophilins as Modulators of Viral Replication

Abstract

Cyclophilins are peptidyl‐prolyl cis/trans isomerases important in the proper folding of certain proteins. Mounting evidence supports varied roles of cyclophilins, either positive or negative, in the life cycles of diverse viruses, but the nature and mechanisms of these roles are yet to be defined. The potential for cyclophilins to serve as a drug target for antiviral therapy is evidenced by the success of non-immunosuppressive cyclophilin inhibitors (CPIs), including Alisporivir, in clinical trials targeting hepatitis C virus infection. In addition, as cyclophilins are implicated in the predisposition to, or severity of, various diseases, the ability to specifically and effectively modulate their function will prove increasingly useful for disease intervention. In this review, we will summarize the evidence of cyclophilins as key mediators of viral infection and prospective drug targets.

Implication of the Whitefly Bemisia tabaci Cyclophilin B Protein in the Transmission of Tomato yellow leaf curl virus

“…Cyps are important in the proper folding of proteins and as modulators for human virus replication (Frausto et al, 2013). Furthermore, Cyps were shown to interact with the capsid protein of the human immunodeficiency virus type 1 (HIV-1; Schaller et al, 2011) and influenza A virus M1 protein (Liu et al, 2009) and were shown to play a key role in the viral replication cycle.…”

Immunophilin–protein interactions inPlasmodium falciparum

“…Caenorhabditis elegans possesses a number of immunophilin isoforms, many of which have been well-characterized. Immunophilins have a number of known roles in disease, including several viral infections and neurodegenerative diseases, and immunophilin ligands are actively being pursued as novel treatments (Kang et al 2008;Galat and Bua, 2010;Frausto et al 2013). In bacteria, Escherichia coli PPIase SurA is dispensable for growth in culture but required for biogenesis of the pilus that is required for urinary tract invasion (Justice et al 2005), and mutants of Bacillus subtilis with both of the organism's PPIases deleted had much reduced growth under near-starvation conditions (Gothel et al 1998).…”

The future of antivirals

“…The cyclophilins are peptidyl-prolyl cis/transisomerases that are required for the proper folding of certain host proteins [56] and also play an important role in the life cycles of diverse viruses [57]. Cyclosporine A and sanglifehrin A are immunosuppressive molecules that inhibit cyclophilins [58].…”

“…By chemical modification, analogues were generated without immunosuppressive properties. These cyclophilin inhibitors inhibit a broad range of RNA and DNA viruses, both in vitro and in animal models [57]. The most advanced molecules are alisporivir and SCY-635.…”