Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 59, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2022.128575
Keywords
MRGPRX2; Pseudo-allergy; Mubritinib; B10-S; Mast cells
Categories
Funding
- National Natural Science Foundation of China [81930096, 81903573]
- Postdoctoral Research Foun-dation of China [2018M643682]
- Natural Science Basic Research Plan in Shaanxi Province of China [2020JQ-089]
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This study synthesized two novel derivatives by integrating the active substructures of B10-S and mubritinib and evaluated their anti-allergic inhibitory effects. The results showed that both compounds effectively inhibited the release of beta-hexosaminidase and histamine in cells by targeting MRGPRX2 and reduced intracellular Ca2+ levels. Molecular docking analysis also revealed their binding sites on MRGPRX2. These findings may contribute to the development of synthetic molecules with anti-pseudo-allergic activity in the future.
Pseudo-allergic reactions frequently occur following clinical drug use and sometimes even cause mortal danger. Mas-related G-protein-coupled receptor member X2 (MRGPRX2) is a novel receptor that mediates pseudo-allergy and is an important target in the treatment of allergies. However, to date, there are no synthetic small-molecule inhibitors that prevent anaphylactoid reactions through this pathway. Our preliminary research suggested that B10-S and mubritinib effectively inhibited LAD2 cells. Therefore, two novel derivatives were synthesized by integrating the active substructures of B10-S and mubritinib, according to the molecular docking results. The antiallergic inhibitory effects of the two compounds were preliminarily evaluated in vitro using beta-hexosaminidase release, histamine release, and intracellular Ca2+ mobilization assays, and their binding sites on MRGPRX2 were analyzed by molecular docking. Both substances inhibited beta-hexosaminidase and histamine release in LAD2 cells and decreased intracellular Ca2+ by inhibiting MRGPRX2 in MRGPRX2-HEK293 cells treated with C48/80 in a dose-dependent manner. The docking results suggested that the molecules could competitively bind to the active site on MRGPRX2 and Glu141, which were combined by C48/80. Our study indicated that the two compounds have potential anti-allergic properties, which may provide evidence that will facilitate the development of synthetic molecules with anti-pseudo-allergic activity for clinical use in the future.
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