Calcineurin inhibitors and the generalization of the presenting protein strategy

This chapter discusses the recent advancement in taking advantage of the specificity of cyclosporin A (CsA) and FK506 drugs for calcineurin. The highly specific calcineurin inhibitors CsA and FK506 are powerful drugs, which have made organ transplantation far more successful because they inhibit the rejection reaction that would otherwise be launched by the host immune system. The ability of CsA and FK506 to prevent graft rejection by suppression of the immune response has made organ transplantation much more successful. However, because calcineurin plays central roles in many processes outside of the immune system, better calcineurin inhibitors may not make better pharmaceuticals. Instead, pathways that lie downstream of calcineurin are ripe for therapeutic targeting, and better immuno suppressants or drugs that treat cardiac hypertrophy may be developed by targeting such pathways. The chapter also examines the structures of the inhibited calcineurin complexes, as it is the unique mode of action of CsA and FK506 that give these drugs their exquisite specificity. Finally, a generalization of the mode of action of these drugs suggests a new approach for drug development, and these implications are also discussed in the chapter.