A Peptidyl Inhibitor that Blocks Calcineurin–NFAT Interaction and Prevents Acute Lung Injury

Acute
respiratory distress syndrome (ARDS) is an inflammatory lung
disease with a high morbidity and mortality rate, for which no pharmacologic
treatment is currently available. Our previous studies discovered
that a pivotal step in the disease process is the activation of the
nuclear factor of activated T cells (NFAT) c3 in lung macrophages,
suggesting that inhibitors against the upstream protein phosphatase
calcineurin should be effective for prevention/treatment of ARDS.
Herein, we report the development of a highly potent, cell-permeable,
and metabolically stable peptidyl inhibitor, CNI103, which selectively
blocks the interaction between calcineurin and NFATc3, through computational
and medicinal chemistry. CNI103 specifically inhibited calcineurin
signaling in vitro and in vivo and
exhibited a favorable pharmacokinetic profile, broad tissue distribution
following different routes of administration, and minimal toxicity.
Our data indicate that CNI103 is a promising novel treatment for ARDS
and other inflammatory diseases.