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PPIase Inhibitors May Act as Drug Alternatives for Treating FIP

Tanaka Y, Sato Y, Sasaki T.  Feline coronavirus replication is affected by both cyclophilin A and cyclophilin B.  J Gen Virol. 2016 Nov 21.

Feline infectious peritonitis (FIP), which is caused by certain strains of feline coronavirus, is a progressive and almost always fatal disease for which there is currently no cure or effective treatment.   Diagnosis of FIP is devastating to owners who will inevitably lose their cherished cats to this disease.

Genetics, stress, and other infectious diseases appear to play a role in developing FIP.  Certain predisposed cats under physical or environmental stress, and where feline corona virus is present, will have an increased likelihood of developing FIP.

There is an important and unique immunological component to the pathology of the disease and there is evidence that some immunosuppressive drugs may offer hope for a treatment.

In this report, researchers from Nippon Veterinary and Life Science University, Tokyo, Japan investigated the mechanism by which the cyclophilin (Cyp) inhibitor, cyclosporine A (CsA), inhibits replication of some corona viruses, such as FIP. Cyclophilins are peptidyl-prolyl isomerases (PPIase), which are important for various physiological functions, but also appear to be necessary for replication of some corona viruses.  When CsA binds to cyclophilin, the complex inhibits calcineurin, a calcium-dependent enzyme that is important in T-cell activation.

By knocking out expression of two cyclophilin isoforms, CypA and CypB, the researchers showed that both cyclophilin isoforms are required for efficient viral replication in FIP-infected cells.  In addition, expression of mutant CypA and CypB with predicted mutations in the PPIase active sites decreased viral replication in FIP-infected cells.  Mutations at PPIase active sites drastically reduced the affinities between CsA and CypA, further supporting the importance of the PPIase active sites for viral replication.

These findings suggest that PPIase active sites of Cyps are required for FCoV replication.  Potential therapeutic effects of PPIase inhibitors, such as CsA, in combination with other therapeutic agents should be further evaluated and determine the possible role of CsA, or other PPIase inhibitors, as part of a FIP treatment cocktail. [GO]

See also:
Tanaka Y, Sato Y, Sasaki T. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses. 2013 May 22;5(5):1250-60.