A novel Lyn-binding peptide inhibitor blocks eosinophil differentiation, survival, and airway eosinophilic inflammation.
Receptor antagonists block all receptor-coupled signaling pathways indiscriminately. We introduce a novel class of peptide inhibitors that is designed to block a specific signal from a receptor while keeping other signals intact. 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 receptor 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 enable 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 on the proliferation of B cells and T cells. To our knowledge, this is the first report on an inhibitor of IL-5 that blocks eosinophil differentiation, survival, and airway eosinophilic inflammation. This novel strategy to develop peptide inhibitors can be applied to other receptors.
Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Medical Branch, Galveston 77555, USA.
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D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D001980:Bronchi / Q000201:enzymology / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053648:Cytokine Receptor Common beta Subunit; D004789:Enzyme Activation / Q000187:drug effects; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000201:enzymology / Q000473:pathology*; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D015848:Interleukin-5 / Q000502:physiology; D053614:Janus Kinase 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D016185:Receptors, Interleukin-3 / Q000502:physiology; D012260:Ribonucleases; D015398:Signal Transduction / Q000187:drug effects; D013229:Stearic Acids / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D001798:Blood Proteins; C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D047091:Eosinophil Granule Proteins; D006131:Growth Inhibitors; D015848:Interleukin-5; D016376:Oligonucleotides, Antisense; D010455:Peptides; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D013229:Stearic Acids; C031183:stearic acid; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D019061:src-Family Kinases; D012260:Ribonucleases