A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation, survival, and airway eosinophilic inflammation

Receptor antagonists block all receptor-coupled signaling pathways indiscri minately. We introduce a novel class of peptide inhibitors that is designed to block a specific signal from a receptor while keeping other signals int act. This concept was tested in the model of IL-5 signaling via Lyn kinase. We have, previously mapped the Lyn-binding site of the IL-5/GM-CSF recepto r common beta (beta c) subunit, In the present study, we designed a peptide inhibitor using the Lyn-binding sequence. The peptide was N-stearated to e nable cellular internalization The stearated peptide blocked the binding of Lyn to the beta c receptor and the activation of Lyn, The lipopeptide did not affect the activation of Janus kinase 2 or its association with beta c. The inhibitor blocked the Lyn-dependent functions of IL-5 in vitro (e.g., eosinophil differentiation from stem cells and eosinophil survival). It did not affect eosinophil degranulation. When applied in vivo, the Lyn-binding peptide significantly inhibited airway eosinophil influx in a mouse model of asthma. The lipopeptide had no effect on basophil histamine release or o n the proliferation of B cells and T cells, To our knowledge, this is the f irst report on an inhibitor of IL-5 that blocks eosinophil differentiation, survival, and airway eosinophilic inflammation, This novel strategy to dev elop peptide inhibitors can be applied to other receptors.