CsAcyclophilin

CsAcyclophilin is the complex formed by cyclosporin A (CsA) and cyclophilin, a family of cytosolic peptidyl-prolyl cis-trans isomerases present in many organisms. The CsA–cyclophilin complex is the pharmacologically active species responsible for most of the immunosuppressive effects of CsA.

Mechanism of action: The CsA–cyclophilin complex binds to calcineurin, a calcium/calmodulin-dependent serine/threonine phosphatase, inhibiting its phosphatase activity. This prevents dephosphorylation and activation of NFAT transcription factors, reducing transcription of interleukin-2 and other cytokines in T cells and thereby suppressing T-cell activation and the adaptive immune response.

Chemistry and binding: CsA is a cyclic peptide of 11 amino acids; its binding to cyclophilin generates a conformationally active complex that interacts with calcineurin. The interaction is highly specific and essential to the drug’s immunosuppressive effect.

Clinical use and pharmacology: The CsA–cyclophilin complex is the principal mechanism of action behind cyclosporin A’s use in organ transplantation to prevent rejection. CsA is used in various autoimmune disorders and is administered orally or intravenously; dosing is individualized. It has a narrow therapeutic window and significant drug interactions, largely via CYP3A4 metabolism. Adverse effects include nephrotoxicity, hypertension, neurotoxicity, hepatotoxicity, hyperlipidemia, and increased risk of infection and malignancy.

History: Cyclosporin A was discovered in the 1970s from the fungus Tolypocladium inflatum and developed as an immunosuppressant by pharmaceutical companies; the identification of cyclophilin as its target helped explain its mechanism.