Asthma is a chronic disease of the lungs affecting a growing population worldwide and is characterized by TH2 cell-based inflammation. Patients express elevated levels of IL-4 and IL-13 in their airways which signal through the JAK/STAT6 pathway and lead to airway constriction, increased mucus expression, and eosinophilia, the hallmarks of the disease. We are developing phosphopeptide mimics targeted to the SH2 domain of STAT6 to prevent docking to cytokine receptors and activation (phosphorylation of Tyr641) and thereby inhibit the transcription of asthma-causing genes. Structure-affinity studies with phosphopeptides and related mimics were conducted. From these, twenty phosphatase-stable, cell-permeable phosphopeptide mimetic prodrugs were synthesized and screened for the ability to inhibit IL-4 stimulated STAT6 phosphorylation in immortalized human airway epithelial cells. In vivo, lead candidate PM-43I very potently blocked the induction of fungal-induced asthma, and as a therapeutic, reversed established disease at 5 ng doses using aerosol delivery. Importantly, PM-43I did not impair the ability of the mice to fight influenza and fungal infections. Intranasal delivery of PM-43I did not block TH2 cell sensitization to the experimental allergen, ovalbumin, delivered intraperitoneally. The toxicity profile was outstanding. Intranasal delivery of PM-43I 3ᵡ/week for 7 months did not affect blood chemistry, complete blood counts, and organ morphology. The drug is eliminated in the urine. Taken together, these results suggest that on delivery to the lung, the phosphonate blocking groups are cleaved and the resulting negatively charged phosphopeptide mimic does not enter cells in the body outside the lung. Conclusion: phosphonate prodrugs targeted to the SH2 domain of STAT6 potently reverse asthma symptoms, are restricted to the lung, and do not cause systemic immune suppression, a drawback of standard-of-care inhaled corticosteroids.