Structure-based rationale for interleukin 5 receptor antagonism.
Human interleukin 5 (IL5) is the major hematopoietin that stimulates the proliferation, migration and activation of eosinophils and is implicated in the pathogenesis of inflammatory and other myeloproliferative diseases. IL5 functions through the signaling of a common receptor subunit beta (beta c), in a receptor activation process that requires initial recruitment of an IL5 specific receptor subunit alpha (IL5Ralpha), for cytokine presentation to beta c. Important advances have been made to understand molecular mechanisms of cytokine recognition and receptor antagonism. Mutational studies indicate that a pair of charge complementary regions play an essential role in specific interaction between IL5Ralpha and IL5. Moreover, peptide studies with the IL5 system have identified a cyclic peptide inhibitor, AF17121, which binds specifically to IL5Ralpha by mimicking the cytokine. A key receptor-recognition pharmacophore has been identified in this peptide inhibitor, and sites of inhibitor recognition can be proposed in the homology-deduced structural model of IL5Ralpha. These results provide an experimental platform to derive enhanced-potency peptidomimetic inhibitors. Such inhibitors have potential use as tools to evaluate the role of eosinophilia in disease and as potential leads to antagonists to treat hyper-eosinophilic diseases such as eosinophilic esophagitis, asthma and chronic myeloproliferative leukemias.
Ishino
Tetsuya
T
Drexel University College of Medicine, Department of Biochemistry and Molecular Biology, Philadelphia, PA 19102-1192, USA.
Harrington
Adrian E
AE
Gopi
Hosahudya
H
Chaiken
Irwin
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001665:Binding Sites; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology; D004804:Eosinophils / Q000502:physiology; D006801:Humans; D015848:Interleukin-5 / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D053666:Interleukin-5 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation
C509414:AF17121 peptide; D000911:Antibodies, Monoclonal; C485918:IL5RA protein, human; D015848:Interleukin-5; D053666:Interleukin-5 Receptor alpha Subunit; D010456:Peptides, Cyclic