Orai1 is a Ca2+ channel in a murine allergic asthma model in the plasma membrane that regulates inflammation and mediates store-operated Ca2+ entry (SOCE). SPLUNC1 (short palate lung and nasal epithelial clone is an asthma gene modulator that inhibits Orai1/SOCE by binding to its C-terminal 6 region. In asthmatic patients’ airways, SPLUNC1 levels are reduced. Researchers anticipated that inhaled 6 peptidomimetics could inhibit Orai1 and reduce airway inflammation in a mouse asthma model. Ca2+ signaling, Förster resonance energy transfer (FRET), fluorescence recovery after photobleaching, immunostaining, total internal reflection (TIRF) microscopy, and Western blotting were all utilized to assess 6-Orai1 relationships. 

Wild-type and SPLUNC1-/- mice were treated to house dust mite (HDM) extract peptide 6 peptides to see if 6 peptidomimetics inhibited SOCE and reduced inflammation in vivo. They tested 6 for inhalation using nebulization, jet milling, and scanning electron microscopy. The response to HDM was enhanced in SPLUNC1-/- mice. Orai1 levels rose in BAL-derived immune cells in SPLUNC1-/- mice but not in wild-type mice following HDM exposure. Regardless of genotype, inhaled 6 reduced Orai1 levels in mice. Six decreased eosinophilia and neutrophilia in HDM-exposed mice in a dose-dependent manner. Six reduced SOCE in various immune cell types in vitro, and it could be nebulized or jet-milled without losing activity. These findings imply that 6 peptidomimetics could be a promising anti-inflammatory treatment for asthma patients.