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A7702 - Small Molecule Mimetics of α-Helical Domain of IRAK2 Attenuate the Pro-Inflammatory Effects of IL-33 in an Asthma-Like Mouse Model
Author Block: J. Li1, K. Saruta2, J. Dumouchel1, J. Magat1, J. Thomas1, D. Ajami2, M. Rebek2, J. Rebek2; 1University of California San Diego, La Jolla, CA, United States, 2The Scripps Research Institute, La Jolla, CA, United States.
RATIONALE: Interleukin-33 (IL-33) and its receptor ST2 play important roles in airway inflammation and contribute to asthma onset and exacerbation. Polymorphisms of IL-33 and ST2 genes are associated with asthma and increased numbers of eosinophils. IL-33 is a contributing factor to airway inflammation and asthma exacerbation. IL-33 loss-of-function mutation reduces blood eosinophil counts and people with this mutation are protected from asthma. Treatment of anti-IL-33 antibody or overexpression of sST2, the decoy receptor for IL-33, in OVA induced mouse asthma model can attenuate asthma severity. IL-33/ST2 signaling pathway recruits adapter protein MyD88 to transduce intracellular signaling and subsequently activates interleukin receptor associated kinases (IRAKs). MyD88 forms a complex with IRAK2 and IRAK4 called the Myddosome (MyD88-IRAK4-IRAK2) and activates NF-kB, MAPKs p38 and JNK. The formation of the Myddosome is important for the signal transduction. The discovery of Myddosome structure has made it a possible target for blocking IL-33/ST2 signaling. METHODS: We established an IL-33 induced asthma-like mouse model and demonstrated that MyD88 knock-out mice were protected from IL-33 induced asthma-like phenotype. We synthesized a series of small molecule mimetics of the α-helical domain of IRAK2, which can compete with IRAK2 to bind MyD88-IRAK4. We studied small molecule mimetics effects on IL-33 induced NF-kB transcriptional activity in vitro, and the lead compound 7004 was studied in the IL-33 induced and the OVA induced asthma-like mouse model in vivo. RESULTS: A series of small molecules were screened using an NF-kB promoter and Co-immunoprecipitation assay in vitro. These mimetics of the α-helical domain of IRAK2 can interfere with the protein-protein interaction between IRAK2 and IRAK4, therefore blocking the binding of IRAK2 to MyD88-IRAK4. The lead compound 7004 can attenuate the pro-inflammatory effects in an asthma-like mouse model in vivo. Our results suggest that MyD88 represents an intracellular therapeutic target, inhibiting downstream signaling cascades and attenuating pro-inflammatory cytokine responses to IL-33. CONCLUSIONS: Our data indicate that small molecule mimetics can penetrate the cell membrane and interrupt Myddosome formation. Interfering with the Myddosome complex formation may provide effective treatment options compared with the antibodies against IL-33 or ST2. There has not been any attempt made to evaluate MyD88 as a potential therapeutic target for asthma. The Myddosome may represent a novel therapeutic target for diseases in which IL-33/ST2 plays important roles, such as asthma and other inflammatory diseases.