Structure-Based Rationale for Interleukin 5 Receptor Antagonism

Authors: Ishino, Tetsuya; Harrington, Adrian E.; Gopi, Hosahudya; Chaiken, Irwin

Source: Current Pharmaceutical Design, Volume 14, Number 12, April 2008 , pp. 1231-1239(9)

Publisher: Bentham Science Publishers

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Abstract:

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 β (βc), in a receptor activation process that requires initial recruitment of an IL5 specific receptor subunit α (IL5Rα), for cytokine presentation to βc. 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 IL5Rα and IL5. Moreover, peptide studies with the IL5 system have identified a cyclic peptide inhibitor, AF17121, which binds specifically to IL5Rα 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 IL5Rα. 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.

Document Type: Research article

Affiliations: 1: Drexel University College of Medicine, Department of Biochemistry and Molecular Biology, 245 North 15th Street, Mall Stop 497, New College Building, Room 11102, Philadelphia,PA 19102-1192, USA.

Publication date: 2008-04-01

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Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.

Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

Structure-Based Rationale for Interleukin 5 Receptor Antagonism

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