Immunophilins complex with immunosuppressant

Another drug whose immunosuppressive action is mediated by the complexation with a cellular protein of the immunophilins is FK506. FK506 binds to proteins of the FKBP family. The complex formed is involved in the inhibition of the phosphatase calcineurin, similar to the mode of action of CsA after binding to cyclophilin. The ACE method was used to detect... 

Cyclosporine provides maintenance immunosuppression by inhibition of the activation of T lymphocytes via a multifaceted mechanism. The drug, a fat soluble 11 amino acid cyclic polypeptide, crosses the lymphocyte membrane freely where it forms a pharmacologically active complex with the intracellular immunophilin receptor cyclophilin. This complex, but not cyclosporine by itself, inhibits the Ca /calmodulin-activated form of serine/threonine phosphatase calcineurin, thereby inhibiting the activation of NFAT cells. The latter action is considered to be the key step... 

As with cyclosporine and Siro, Tac exerts its immunosuppressive effect following the formation of a complex with immunophilins. The complex of Tac and FK-BP12 in lymphocytes suppresses the synthesis of cytokines and inflammatory mediators by the same mechanisms (see Cyclosporine section for details and references). 

Figure 4.9. Schematic representation of immunosuppressant-immunophilin complex interactions. CyPs bind CsA to form a complex in which both components undergo change in structure. This complex binds to, and inhibits, calcineurin (CnA, A subunit CnB, B subunit CaM, camodulin) in a calcium-dependent manner. FK506-binding protein complxes with FK506 or rapamycin (Rapa). FKBP-FK506 also binds calcineurin. The target of FKBP-rapamycin is unknown but is presumed to be different from cacineurin.

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