Structure-Based Rationale for Interleukin 5 Receptor Antagonism

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 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.

Interleukin-5 in the Pathophysiology of Severe Asthma

“…(JAK)2, whereas the βc subunit is associated with JAK1 (Kouro and Takatsu, 2009). When IL-5 is present, it binds to IL-5Rα and drives the constitution of a functional IL-5Rα/βc receptor complex, which is responsible for the activation of an intricate network of signaling pathways (Figure 2; Johanson et al, 1995;Ishino et al, 2008;Molfino et al, 2012). In particular, binding of IL-5 to IL-5Rα sequentially activates JAK2 and signal transducers and activators of transcription (STAT)1, 3, and 5, which in turn stimulate the transcriptional functions of many genes involved in eosinophil proliferation, including pim-1 and cyclin D3 (Pazdrak et al, 1995;Stout et al, 2004).…”

Severe eosinophilic asthma: from the pathogenic role of interleukin-5 to the therapeutic action of mepolizumab

“… 35 When IL-5 binds to IL-5Rα, this interaction triggers the assembly of a functional IL-5Rα-βc receptor unit that drives the activation of a complex signal transduction network, including several different components. 15 , 36 , 37 In particular, upon IL-5-mediated activation, JAK2 in turn stimulates the transcriptional functions of signal transducers and activators of transcription (STAT)1, 3, and 5, which increase the expression rates of several genes implicated in eosinophil proliferation such as pim-1 and cyclin D3 ( Figure 1 ). 38 , 39 Furthermore, JAK2 cooperates with Lyn and Raf-1 kinases in mediating the antiapoptotic effect induced by IL-5 on eosinophils, resulting in a significant prolongation of their survival.…”

Molecular and clinical rationale for therapeutic targeting of interleukin‐5 and its receptor

“…Binding of IL‐5 to its receptor subunits involves dynamic conformational changes in binding sites that are specific to the IL‐5 cytokine itself and to IL‐5Rα and βc subunits in terms of amino acid residues, their locations within epitopes and charges. These changes take place during what is essentially a two‐phase process beginning with a high‐affinity binding of IL‐5 to IL‐5Rα, followed by binding of this activated complex to βc to initiate signal transduction . This receptor activation probably involves dimerization of a critical cytoplasmic domain of βc .…”

“…Both IL‐5Rα and βc subunits contain extracellular fibronectin‐III domains, which are characteristically conserved within the class I receptor superfamily (hemopoietin receptor family) in what is sometimes termed a cytokine recognition motif, in terms of IL‐5Rα as well as βc . These motifs are thought to be specific to certain groups of amino acid residues in IL‐5/IL‐5Rα, which may bind either IL‐5 or an antagonist , suggesting the potential to tailor specific molecules for therapeutic intervention.…”