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<p>Histamine H1 receptor antagonists are widely used to treat allergic conditions. As some synthetic drugs in this class are associated with adverse effects, discovering new antagonists from natural sources remains an active pursuit. Efficient screening methods that evaluate receptor function in a physiologically relevant, integrated manner are still needed. In this study, we developed a label-free, cell-based assay to screen for H1 receptor antagonists by monitoring dynamic mass redistribution (DMR) in A431 cells, which endogenously express H1 receptor. After validating the system with reference agonists and antagonists, we screened a panel of 32 natural compounds and identified four initial hits, including the sesquiterpene lactone enhydrin. Enhydrin dose-dependently antagonize‌d histamine-induced DMR responses and downstream p38 MAPK (mitogen-activated protein kinase) phosphorylation, and it prevented agonist-triggered internalization of the H1 receptor. Molecular docking and dynamics simulations supported a direct mechanism, showing that enhydrin forms a stable complex within the receptor binding pocket through sustained interactions with residues including LYS191, ASN198, and TRP428. Our findings establish enhydrin as a promising therapeutic candidate for allergic inflammatory responses by antagonizing the H1 receptor. This study extends the label-free cell-based screening of H1 receptor antagonists, thereby facilitating the discovery of novel anti-allergic agents.</p>

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A label-free cell-based screening identifies enhydrin as a novel natural antagonist of the histamine H1 receptor

  • 期刊论文

  • 发表日期：

    2026年4月12日

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  • Ziwei Zhang,
  • Qichao Hu,
  • Hanzhen Wang,
  • Zhichao Zhou,
  • Zhan Si,
  • Liying Shi

摘要

Histamine H1 receptor antagonists are widely used to treat allergic conditions. As some synthetic drugs in this class are associated with adverse effects, discovering new antagonists from natural sources remains an active pursuit. Efficient screening methods that evaluate receptor function in a physiologically relevant, integrated manner are still needed. In this study, we developed a label-free, cell-based assay to screen for H1 receptor antagonists by monitoring dynamic mass redistribution (DMR) in A431 cells, which endogenously express H1 receptor. After validating the system with reference agonists and antagonists, we screened a panel of 32 natural compounds and identified four initial hits, including the sesquiterpene lactone enhydrin. Enhydrin dose-dependently antagonize‌d histamine-induced DMR responses and downstream p38 MAPK (mitogen-activated protein kinase) phosphorylation, and it prevented agonist-triggered internalization of the H1 receptor. Molecular docking and dynamics simulations supported a direct mechanism, showing that enhydrin forms a stable complex within the receptor binding pocket through sustained interactions with residues including LYS191, ASN198, and TRP428. Our findings establish enhydrin as a promising therapeutic candidate for allergic inflammatory responses by antagonizing the H1 receptor. This study extends the label-free cell-based screening of H1 receptor antagonists, thereby facilitating the discovery of novel anti-allergic agents.