Cyclosporine – An Antiviral Agent

CYCLOSPORINE – AN ANTIVIRAL AGENT?

With the discovery of Cyclosporine in 1971 by biologist Hans Peter Frey, immunopharmacology experienced a new phase. Isolated from the fungus Tolypocladium infatum, was originally used as anti-fungal antibiotic. [1] Used with the role of anti-fungal antibiotic, Cyclosporine demonstrated its very narrow spectrum antibiotic action and clinical application has been limited. In 1976 J.F. Borel discovered the immunosuppressive activity of Cyclosporine. [2][3] This was the first immunosuppressant that allowed selective T cell immunoregulation, without selective toxicity. [4] From that moment, thanks to Cyclosporine, the transplantation has entered into a new era. This decreased morbidity and allowed routine transplantation of organs that until then had been made only experimental. [5]

Cyclosporine A (CsA) is an immunosuppressant drug widely used in organ transplants to prevent rejection of transplanted graft. This reduces the activity of the immune system by interfering with the activity and growth of T cells. [2] [3] Most peptides are synthesized by ribosomes, but Cyclosporine is a cyclic nonribosomal peptide of 11 amino acids and contains a single D-amino acid, which are rarely encountered in nature.[5]

Cyclosporine is used to prevent and treat graft-versus-host disease in bone-marrow transplantation and to prevent rejection of kidney, heart, and liver transplants. [6] [7]

It also treats rheumatoid arthritis and psoriasis[7] and is used as an ophthalmic emulsion for the treatment of dry eyes.[8] In addition to these indications, Cyclosporine is also used in severe atopic dermatitis, Kimura disease, pyoderma gangrenosum, chronic autoimmune urticaria, acute systemic mastocytosis and, infrequently, in rheumatoid arthritis and related diseases, although it is only used in severe cases.[6]

Cyclosporine binds to cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially T cells. This Cyclosporine – cyclophilin complex inhibits calcineurin, which under normal conditions is responsible for transcription activation of interleukin 2 (IL-2). In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T-cells (NFATc), which moves in T cell nucleus and increases the activity of genes encoding IL-2 and related cytokines. Cyclosporine prevents the dephosphorylation of NF-AT by binding to cyclophilin. [9] It also inhibits lymphokine production and interleukin release and, therefore, leads to a reduced function of effector T-cells. It does not affect cytostatic activity.

Cyclosporine influences the mitochondria by preventing the permeability transition of mitochondrial pore opening, thus inhibiting the release of cytochrome C, a powerful stimulating apoptosis factor. Cyclosporine (Cyclosporine A, CsA) has strong immunosuppressant properties, reflecting its ability to block the transcription of genes of cytokines in activated T cells. It is well established that the formation of a complex with CsA by cyclophilin inhibits calcineurin phosphatase activity, which regulates subsequent nuclear translocation and activation of the transcription factors NFAT. [10]

Cyclosporine is very quickly metabolized after ingestion. Resulting metabolites include Cyclosporine B, C, D, E, H, L et al. [11] Metabolites of Cyclosporine have been shown to have immunosuppressive activity less than CsA (about <10%), and are associated with nephrotoxicity, which is why they are used isolated. [12]

In addition to the path calcineurin / NFAT, recent studies indicate that CsA has anti-viral effect anti-HCV. The effect was attributed to inhibition of cyclophilin B (CYP-B), a cellular target of CsA, which regulates the function of the HCV NS5B RNA polymerase, RNA polymerase essential for efficient replication of the viral genome. Thus, the CYP-B action severely inhibited HCV genome replication. [13]

Worldwide more than 130 million people are chronically infected with hepatitis C virus (HCV), an RNA virus of the Flaviviridae family, which causes chronic liver disease, including chronic hepatitis, cirrhosis and hepatocellular carcinoma. [14]

The HCV genome encodes a single polyprotein that is cleaved into at least 10 viral proteins: the structural proteins (core, E1, E2) that constitute the virion, the p7 ion channel, and six nonstructural (NS) proteins (NS2, 3, 4A, 4B, 5A, and 5B). NS3-5B are sufficient to sustain RNA replication. [15] NS2 is a cysteine protease that cleaves the NS2-3 junction and requires an N-terminal part of NS3 as a cofactor and plays a crucial but vaguely defined role during virus assembly. [16][17]

Recently, the impact of CsA on HCV RNA replication and infectivity were studied in cell culture systems which allow full replication cycle of HCV replication in vitro, and in vivo were achieved sustained virological responses to administration of CsA, which showed activity of CsA against viral replication of HCV both in vitro and in vivo. [18][19] The antiviral effect of CsA and its derivatives is related to the ability to interact with cyclophilins (CYP), which in turn have been recognized as cellular cofactors essential for HCV replication. [20][21]

In vitro studies have shown that administration of CsA in doses comparable to therapeutic levels in patients leads to a reduction up to 20% of HCV viral replication. [22]

The two CsA-derivatives Debio-025 and NIM811 lacking anticalcineurin activity (determinant for the immunosuppressive effect of CsA) are now in human trials as HCV inhibitors, with initial data showing good activity and no signs of clinically relevant resistance. [23][24] Because in subgenomic HCV replicons, minimal replicating genomes comprising NS3-NS5B, various viral CsA-resistance mutations were found to map to NS5B and cyclophilin B (CypB) was found to associate with NS5B and to stimulate its RNA binding activity, it is believed that NS5B is the primary target of CsA. [25][26]

High concentrations of CsA decreased RNA replication of both the subgenomic replicon and full-length virus by about 4 times. Sensitivity of the replicon toward CsA was similar to what has been reported. [14]

In vivo studies have shown that Debio-025, a derivative of CsA not only has a synergistic role related to IFN-mediated anti-viral effect. Cyclophilin inhibition by Debio-025 produces an appropriate anti-HCV effect by interacting with RNA dependent by RNA polymerase. [27]

CsA was initially used due to its immunosuppressive role, and then, clinical studies have shown that CsA has a potent anti-HCV effect. [28] Patients who were treated with CsA for its immunosuppressive role have achieved a sustained virological response in 46% of the total cases. [26] Side effects such as hypertension, neurotoxicity and nephrotoxicity have made use of CsA in anti-HCV therapeutic purposes be limited. [29]

The anti-NS2 activity of CsA provides a rationale to test combinations of CsA-derivatives with novel antivirals targeting other components of the HCV replication machinery. Future clinical studies should address the benefits of this combination therapy in vivo and future laboratory work in vitro are needed to determine which function of NS2 is inhibited by CsA.

Based on the observed effects of CsA on HCV viral replication both in vitro and in vivo we hope that in the near future CsA or CsA-derivatives can bring, with or without antiviral drugs, an important contribution to the achievement of a new treatment to reduce viral replication of HCV and even stop it. To be successful in this regard it is necessary that large teams of researchers and physicians to work together in the development of cohort studies.

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Neoral Label http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=94461af3-11f1-4670-95d4-2965b9538ae3

Restasis Label http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8e24af2b-bc1c-4849-94f2-6df950cdca89

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