KIRA6 is an Effective and Versatile Mast Cell Inhibitor of IgE-mediated Activation.

Autor: Wunderle V; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany.; Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Wilhelm T; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Boukeileh S; The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel., Goßen J; Institute for Advanced Simulation, Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, Jülich, Germany., Margreiter MA; Institute for Advanced Simulation, Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, Jülich, Germany., Sakurov R; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Capellmann S; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Schwoerer M; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Ahmed N; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Bronneberg G; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Arock M; Department of Hematological Biology, Pitié-Salpêtrière Charles-Foix Hospital, AP-HP Sorbonne University, Paris, France., Martin C; Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany., Schubert T; 2bind, Regensburg, Germany., Levi-Schaffer F; The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel., Rossetti G; Institute for Advanced Simulation, Jülich Supercomputing Centre, Forschungszentrum Jülich GmbH, Jülich, Germany.; Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich GmbH, Jülich, Germany.; Department of Neurology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany., Tirosh B; The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.; Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA., Huber M; Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Jazyk: angličtina
Zdroj: European journal of immunology [Eur J Immunol] 2024 Dec 15, pp. e202451348. Date of Electronic Publication: 2024 Dec 15.
DOI: 10.1002/eji.202451348
Abstrakt: 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.
(© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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