Inhibitors of the calcineurin/NFAT pathway.
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. Although the use of these drugs has been crucial for the success of organ transplantation, their therapeutic use is associated with severe side effects. There is, therefore a need to develop better, less toxic immunosuppressive agents. In recent years, a number of endogenous calcineurin inhibitor proteins have been identified that bind calcineurin and block its phosphatase activity. In some cases the calcineurin interaction domains of these proteins, or their corresponding docking sites on calcineurin, have been described. However, their mode of action and regulatory mechanisms are not completely known. 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.
Martínez-Martínez
Sara
S
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, Spain.
Redondo
Juan Miguel
JM
D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008954:Models, Biological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015398:Signal Transduction / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D065095:Calcineurin Inhibitors; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus