Novel small molecule MRGPRX2 antagonists inhibit a murine model of allergic reaction.

Autor: Kumar M; School of Biological Sciences, University of Hong Kong, Hong Kong SAR., Duraisamy K; School of Biological Sciences, University of Hong Kong, Hong Kong SAR., Annapureddy RR; Department of Chemistry, Ludwig-Maximilians-Universität, Munich, Germany., Chan CB; School of Biological Sciences, University of Hong Kong, Hong Kong SAR., Chow BKC; School of Biological Sciences, University of Hong Kong, Hong Kong SAR. Electronic address: bkcc@hku.hk.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2023 Apr; Vol. 151 (4), pp. 1110-1122. Date of Electronic Publication: 2022 Dec 26.
DOI: 10.1016/j.jaci.2022.12.805
Abstrakt: Background: Activation of Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial non-IgE pathway for mast cell activation associated with allergic reactions and inflammation. Only a few peptides and small compounds targeting MRGPRX2 have been reported, with limited information on their pharmacologic activity.
Objective: We sought to develop novel small molecule MRGPRX2 antagonists to treat MRGPRX2-mediated allergies and inflammation.
Methods: A computational approach was used to design novel small molecules as MRGPRX2 antagonists. The short-listed molecules were synthesized and characterized by liquid chromatography and mass spectrometry as well as nuclear magnetic resonance. Inhibitory activity on MRGPRX2 signaling was assessed in vitro by using functional bioassays (β-hexosaminidase, calcium flux, and chemokine synthesis) and receptor activation assays (β-arrestin recruitment and Western blot analysis) in human LAD-2 mast cells and HTLA cells. In vivo effects of the novel MRGPRX2 antagonists were assessed using a mouse model of acute allergy and systemic anaphylaxis.
Results: The novel small molecules demonstrated higher binding affinity with MRGPRX2 in the docking study. The half-maximal inhibitory concentration is in the low micromolar range (5-21 μM). The small molecules inhibited not only the early phase of mast cell activation but also the late phase, associated with chemokine and prostaglandin release. Further, Western blot analysis revealed inhibition of downstream phospholipase C-γ, extracellular signal-regulated protein kinase 1/2, and Akt signaling pathway. Moreover, in the mouse models of allergies, small molecule administration effectively blocks acute, systemic allergic reactions and inflammation and prevents systemic anaphylaxis.
Conclusion: The small molecules might hold a significant therapeutic promise to treat MRGPRX2-mediated allergies and inflammation.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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