Current medicinal chemistry
-
The well known calcium-sensitive phosphatase calcineurin is implicated in many eukaryotic activation and developmental programmes, including lymphocyte activation, heart-valve morphogenesis, angiogenesis, and neural and muscle development. The importance of this phosphatase is graphically illustrated by the observation that the immunosuppressive actions of the microbial drugs Cyclosporin A (CsA) and FK506 arise from their inhibition of calcineurin. As substrates of calcineurin, transcription factors of the NFAT family play an essential role in lymphocyte activation, and it follows that their function is also inhibited by CsA and FK506. ⋯ In a more recent development, specific amino acidic sequences implicated in the interaction between calcineurin and NFAT have been identified. It is of special interest that specific disruption of this pathway has been obtained through the expression of peptides based on some of these sequences. A more profound analysis of these issues could open up new perspectives in immunosuppressive therapy; promising compounds with features of endogenous calcineurin inhibitors (and thus likely to have fewer toxic effects than CsA and FK506), or selective blockers of calcineurin-NFAT interactions that would not alter the functioning of other calcineurin substrates.