Affinity-driven peptide selection of an NFAT inhibitor more selective thancyclosporin A

The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on int eraction between the phosphatase calcineurin and the transcription factor N FAT. A high-affinity calcineurin-binding peptide was selected from combinat orial peptide Libraries based on the calcineurin docking motif of NFAT, Thi s peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression o f other cytokines that require calcineurin but not NFAT. Substitution of th e optimized peptide sequence into the natural calcineurin docking site incr eased the calcineurin responsiveness of NFAT. Compounds that interfere sele ctively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are Less tox ic than current drugs.