KIRA6 是一种有效的多用途肥大细胞抑制剂,能抑制 IgE 介导的活化。

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Veronika Wunderle, Thomas Wilhelm, Shatha Boukeileh, Jonas Goßen, Michael A Margreiter, Roman Sakurov, Sandro Capellmann, Maike Schwoerer, Nabil Ahmed, Gina Bronneberg, Michel Arock, Christian Martin, Thomas Schubert, Francesca Levi-Schaffer, Giulia Rossetti, Boaz Tirosh, Michael Huber
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引用次数: 0

摘要

肥大细胞(MC)驱动的过敏性疾病在不断扩大,需要开发新型药理学 MC 稳定剂。过敏原/抗原(Ag)通过交联 IgE 的高亲和力受体(FcεRI)触发的活化从根本上受 SRC 家族激酶(如 LYN 和 FYN)的调控,这些激酶表现出积极和消极的功能。我们报告了内质网应激传感器 IRE1α 的抑制剂 KIRA6 通过抑制 LYN 和 FYN 来抑制 IgE 介导的 MC 激活。KIRA6 可减轻 Ag 刺激的早期信号传导和效应器功能,如小鼠骨髓来源 MC 的脱颗粒和促炎细胞因子的产生/分泌。此外,KIRA6 还抑制了体内外模型中 Ag 引发的支气管收缩和 IgE 介导的人 MCs 刺激。我们通过同源建模和分子动力学模拟评估了 KIRA6 与三种与 MC 相关的酪氨酸激酶(LYN、FYN 和 KIT)的相互作用,以及 KIRA6 结构作为开发单特异性、双特异性或三特异性抑制剂的药代动力学潜力。我们发现,KIRA6 与处于非活性状态的 LYN、FYN 和 KIT 的结合力特别强,亲和力相当。总之,我们的数据表明,KIRA6 的化学结构作为一种药源,可以进一步开发,以获得一种有效的 MC 稳定剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation.

Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN. KIRA6 attenuates Ag-stimulated early signaling and effector functions such as degranulation and proinflammatory cytokine production/secretion in murine bone marrow-derived MCs. Moreover, Ag-triggered bronchoconstriction in an ex vivo model and IgE-mediated stimulation of human MCs were repressed by KIRA6. The interaction of KIRA6 with three MC-relevant tyrosine kinases, LYN, FYN, and KIT, and the potential of KIRA6 structure as a pharmacophore for the development of respective single-, dual-, or triple-specificity inhibitors, was evaluated by homology modeling and molecular dynamics simulations. We found that KIRA6 particularly strongly binds the inactive state of LYN, FYN, and KIT with comparable affinities. In conclusion, our data suggest that the chemical structure of KIRA6 as a pharmacophore can be further developed to obtain an effective MC stabilizer.

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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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