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Development of an environmentally sensitive fluorescent peptide probe for MrgX2 and application in ligand screening of peptide antibiotics
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2024-01-25 , DOI: 10.1016/j.jconrel.2024.01.040 Yajing Hou 1 , Jiayu Lu 2 , Mengyao Yi 2 , Xia Cui 1 , Lu Cao 1 , Xianpeng Shi 1 , Pengchong Wang 1 , Nan Zhou 1 , Peng Zhang 1 , Cheng Wang 2 , Huaizhen He 2 , Delu Che 3
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2024-01-25 , DOI: 10.1016/j.jconrel.2024.01.040 Yajing Hou 1 , Jiayu Lu 2 , Mengyao Yi 2 , Xia Cui 1 , Lu Cao 1 , Xianpeng Shi 1 , Pengchong Wang 1 , Nan Zhou 1 , Peng Zhang 1 , Cheng Wang 2 , Huaizhen He 2 , Delu Che 3
Affiliation
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Mast cells (MCs) are primary effector cells involved in immediate allergic reactions. Mas-related G protein-coupled receptor-X2 (MrgX2), which is highly expressed on MCs, is involved in receptor-mediated drug-induced pseudo-anaphylaxis. Many small-molecule drugs and peptides activate MrgX2, resulting in MC activation and allergic reactions. Although small-molecule drugs can be identified using existing MrgX2 ligand-screening systems, there is still a lack of effective means to screen peptide ligands. In this study, to screen for peptide drugs, the MrgX2 high-affinity endogenous peptide ligand substance P (SP) was used as a recognition group to design a fluorescent peptide probe. Spectroscopic properties and fluorescence imaging of the probe were assessed. The probe was then used to screen for MrgX2 agonists among peptide antibiotics. In addition, the effects of peptide antibiotics on MrgX2 activation were investigated in vivo and in vitro. The environment-sensitive property of the probe was revealed by the dramatic increase in fluorescence intensity after binding to the hydrophobic ligand-binding domain of MrgX2. Based on these characteristics, it can be used for in situ selective visualization of MrgX2 in live cells. The probe was used to screen ten types of peptide antibiotics, and we found that caspofungin and bacitracin could compete with the probe and are hence potential ligands of MrgX2. Pharmacological experiments confirmed this hypothesis; caspofungin and bacitracin activated MCs via MrgX2 in vitro and induced local anaphylaxis in mice. Our research can be expected to provide new ideas for screening MrgX2 peptide ligands and reveal the mechanisms of adverse reactions caused by peptide drugs, thereby laying the foundation for improving their clinical safety.
中文翻译：
MrgX2环境敏感荧光肽探针的研制及其在肽类抗生素配体筛选中的应用
肥大细胞（MC）是参与即时过敏反应的主要效应细胞。 Mas 相关 G 蛋白偶联受体-X2 (MrgX2) 在 MC 上高表达，参与受体介导的药物诱导的假性过敏反应。许多小分子药物和肽会激活MrgX2，导致MC激活和过敏反应。尽管利用现有的MrgX2配体筛选系统可以鉴定小分子药物，但仍缺乏筛选肽配体的有效手段。本研究以MrgX2高亲和力内源性肽配体P（SP）为识别基团，设计荧光肽探针，筛选肽类药物。评估了探针的光谱特性和荧光成像。然后使用该探针筛选肽类抗生素中的 MrgX2 激动剂。此外，在体内和体外研究了肽类抗生素对 MrgX2 激活的影响。与MrgX2的疏水性配体结合域结合后荧光强度的急剧增加揭示了探针的环境敏感性。基于这些特性，它可用于活细胞中 MrgX2 的原位选择性可视化。该探针用于筛选10种肽类抗生素，我们发现卡泊芬净和杆菌肽可以与该探针竞争，因此是MrgX2的潜在配体。药理学实验证实了这一假设；卡泊芬净和杆菌肽在体外通过 MrgX2 激活 MC，并诱导小鼠局部过敏反应。我们的研究有望为筛选MrgX2肽配体提供新思路，揭示肽类药物引起不良反应的机制，从而为提高其临床安全性奠定基础。
更新日期：2024-01-25
中文翻译：
MrgX2环境敏感荧光肽探针的研制及其在肽类抗生素配体筛选中的应用
肥大细胞（MC）是参与即时过敏反应的主要效应细胞。 Mas 相关 G 蛋白偶联受体-X2 (MrgX2) 在 MC 上高表达，参与受体介导的药物诱导的假性过敏反应。许多小分子药物和肽会激活MrgX2，导致MC激活和过敏反应。尽管利用现有的MrgX2配体筛选系统可以鉴定小分子药物，但仍缺乏筛选肽配体的有效手段。本研究以MrgX2高亲和力内源性肽配体P（SP）为识别基团，设计荧光肽探针，筛选肽类药物。评估了探针的光谱特性和荧光成像。然后使用该探针筛选肽类抗生素中的 MrgX2 激动剂。此外，在体内和体外研究了肽类抗生素对 MrgX2 激活的影响。与MrgX2的疏水性配体结合域结合后荧光强度的急剧增加揭示了探针的环境敏感性。基于这些特性，它可用于活细胞中 MrgX2 的原位选择性可视化。该探针用于筛选10种肽类抗生素，我们发现卡泊芬净和杆菌肽可以与该探针竞争，因此是MrgX2的潜在配体。药理学实验证实了这一假设；卡泊芬净和杆菌肽在体外通过 MrgX2 激活 MC，并诱导小鼠局部过敏反应。我们的研究有望为筛选MrgX2肽配体提供新思路，揭示肽类药物引起不良反应的机制，从而为提高其临床安全性奠定基础。
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