Which immunosuppressant acts as a calcineurin inhibitor and forms a complex with cyclophilin to inhibit T-cell activation?

Explanation

## Calcineurin Inhibitors: Mechanism and Classification **Key Point:** Cyclosporine is a calcineurin inhibitor that binds to cyclophilin, a cytoplasmic protein, forming a complex that inhibits calcineurin phosphatase activity. ### Mechanism of Action 1. Cyclosporine binds to **cyclophilin** (an intracellular immunophilin) 2. The cyclosporine-cyclophilin complex inhibits **calcineurin** (protein phosphatase 2B) 3. Calcineurin cannot dephosphorylate NFAT (nuclear factor of activated T cells) 4. NFAT remains phosphorylated and cannot enter the nucleus 5. IL-2 and other T-cell cytokine genes are not transcribed 6. T-cell activation and proliferation are blocked **High-Yield:** Cyclosporine is a **11-amino acid cyclic peptide** derived from the fungus *Tolypocladium inflatum*. It is lipophilic and requires microemulsion or lipid-based formulation for absorption. ### Comparison with Other Immunosuppressants | Drug | Mechanism | Immunophilin Binding | Target | | --- | --- | --- | --- | | **Cyclosporine** | Calcineurin inhibition | Cyclophilin | NFAT dephosphorylation | | **Tacrolimus** | Calcineurin inhibition | FK-binding protein (FKBP) | NFAT dephosphorylation | | **Mycophenolate mofetil** | Inosine monophosphate dehydrogenase (IMPDH) inhibition | None | Guanine nucleotide synthesis | | **Azathioprine** | Purine analog | None | DNA/RNA synthesis | **Clinical Pearl:** Although both cyclosporine and tacrolimus inhibit calcineurin, they bind different immunophilins—cyclosporine binds cyclophilin, while tacrolimus binds FKBP12. This distinction is clinically important for drug interactions and side effect profiles. **Mnemonic:** **CyCLO-cyclophilin** — Cyclosporine binds CYCLOphilin.