Structure-Based Optimization of a Peptidyl Inhibitor against Calcineurin-Nuclear Factor of Activated T Cell (NFAT) Interaction

Calcineurin inhibitors such as cyclosporine A and FK506 are effective immunosuppressants but produce severe side effects. Rational modification of a previously reported peptide inhibitor, GPHPVIVITGPHEE (<i>K</i>_D ∼ 500 nM), by replacing the two valine residues with <i>tert</i>-leucine and the C-terminal proline with a <i>cis</i>-proline analogue, gave an improved inhibitor ZIZIT-<i>cis</i>Pro, which binds to calcineurin with a <i>K</i>_D value of 2.6 nM and is more resistant to proteolysis