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.
Adachi
T
T
Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Medical Branch, Galveston 77555, USA.
Stafford
S
S
Sur
S
S
Alam
R
R
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