Kadler Raechel, Morrison Breanna, Yanagihara Angel Anne
Department of Tropical Medicine, Medical Microbiology, and Pharmacology, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI 96822, USA.
Department of Public Health, University of Birmingham, Birmingham B15 2TT, UK.
Toxins (Basel). 2025 Apr 8;17(4):188. doi: 10.3390/toxins17040188.
Examination of venom constituent bioactivities from diverse venomous animals shows certain highly conserved classes, including enzymes (e.g., phospholipases and metalloproteinases) and pore-forming proteins. While antivenoms targeting other unique and lethal venom components have proven to be life-saving, venom-enzyme-driven tissue damage and morbidity persists. Broad-acting enzyme inhibitors demonstrate the potential to augment antivenom approaches. In this study, we investigate the potential utility of certain broad-acting inhibitors in cubozoa for the first time. Fluorogenic assays were used to determine the phospholipase A (PLA) and matrix metalloproteinase (MMP) activity of the Hawaiian box jellyfish, , and this was compared to representative elapid, viper, and bee venoms. In vitro, evaluation of selected small-molecule inhibitors demonstrated the ability and feasibility of the broad-acting therapeutic doxycycline, which inhibited the PLA and MMP activity of (approximately 50% reduction at 0.1 mM (95% CI 0.06-0.15) and 2.1 mM (95% CI 1.4-3.0), respectively), in addition to both snake venoms. Additionally, copper gluconate broadly inhibited the PLA activity of bee, snake, and jellyfish venoms. While all venoms are complex mixtures of bioactive molecules, these studies demonstrate that targeting common class components with broad-acting inhibitors shows promise in clinical and preclinical management.
对多种有毒动物毒液成分生物活性的研究表明，存在某些高度保守的类别，包括酶（如磷脂酶和金属蛋白酶）和成孔蛋白。虽然针对其他独特且致命的毒液成分的抗蛇毒血清已被证明能挽救生命，但毒液酶驱动的组织损伤和发病率仍然存在。广谱作用的酶抑制剂显示出增强抗蛇毒血清方法的潜力。在本研究中，我们首次研究了某些广谱作用抑制剂在立方水母毒液中的潜在效用。采用荧光测定法来测定夏威夷箱形水母毒液的磷脂酶A（PLA）和基质金属蛋白酶（MMP）活性，并将其与代表性的眼镜蛇科动物、蝰蛇和蜜蜂毒液进行比较。在体外，对选定的小分子抑制剂的评估表明，广谱治疗药物强力霉素具有抑制夏威夷箱形水母毒液的PLA和MMP活性的能力和可行性（在0.1 mM（95%置信区间0.06 - 0.15）和2.1 mM（95%置信区间1.4 - 3.0）时分别约降低50%），此外对两种蛇毒也有抑制作用。此外，葡萄糖酸铜广泛抑制蜜蜂、蛇和水母毒液的PLA活性。虽然所有毒液都是生物活性分子的复杂混合物，但这些研究表明，用广谱作用抑制剂靶向常见类别成分在临床和临床前管理中显示出前景。
