Envenoming by snakebite is an important global health issue that has received little attention, leading the World Health Organization to naming it as neglected tropical disease. Several snakebites present serious local symptoms manifested on victims that may not be efficiently neutralized by serum therapy. Phospholipase A2-like (PLA2-like) toxins are present in Viperidae venoms and are responsible for local myotoxic activity. Herein, we investigated the association between BthTX-I toxin and caftaric acid (CFT), a molecule present in plants. CFT neutralized neuromuscular blocking and muscle-damaging activities promoted by BthTX-I. Calorimetric and light-scattering assays demonstrated that CFT inhibitor interacted with dimeric BthTX-I. Bioinformatics simulations indicated that CFT inhibitor binds to the toxin's hydrophobic channel (HCh). According to the current myotoxic mechanism, three different regions of PLA2-like toxins have specific tasks: protein allosteric activation (HCh), membrane dockage (MDoS), and membrane rupture (MDiS). We propose CFT inhibitor interferes with the allosteric activation, which is related to the conformation change leading to the exposure/alignment of MDoS/MDiS region. This is the first report of a PLA2-like toxin fully inhibited by a compound that interacts only with its HCh region. Thus, CFT is a novel candidate to complement serum therapy and improve the treatment of snakebite.

中文翻译：

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Caftaric acid（一种新型的有效的卵磷脂肌毒性抑制剂）中和了类人PLA2蛋白质。

毒蛇咬伤是一个重要的全球性健康问题，很少引起关注，导致世界卫生组织将其命名为被忽视的热带病。几种蛇咬会在受害者身上表现出严重的局部症状，而血清疗法可能无法有效地中和。磷脂酶A2样（PLA2样）毒素存在于蛇蝎毒液中，负责局部肌毒性活性。在本文中，我们研究了BthTX-1毒素与植物中存在的一种分子caftaric acid（CFT）之间的关联。CFT中和了BthTX-1促进的神经肌肉阻滞和破坏肌肉的活动。量热和光散射测定表明CFT抑制剂与二聚体BthTX-1相互作用。生物信息学模拟表明CFT抑制剂与毒素的疏水通道（HCh）结合。根据当前的肌毒性机制，类PLA2毒素的三个不同区域具有特定的任务：蛋白质变构激活（HCh），膜对接（MDoS）和膜破裂（MDiS）。我们建议CFT抑制剂干扰变构活化，这与导致MDoS / MDiS区域暴露/排列的构象变化有关。这是首次报道PLA2样毒素完全被仅与其六氯环己烷区域相互作用的化合物所抑制。因此，CFT是补充血清治疗和改善蛇咬伤治疗的新型候选药物。这与导致MDoS / MDiS区域曝光/对准的构象变化有关。这是首次报道PLA2样毒素完全被仅与其六氯环己烷区域相互作用的化合物所抑制。因此，CFT是补充血清治疗和改善蛇咬伤治疗的新型候选药物。这与导致MDoS / MDiS区域曝光/对准的构象变化有关。这是首次报道PLA2样毒素完全被仅与其六氯环己烷区域相互作用的化合物所抑制。因此，CFT是补充血清治疗和改善蛇咬伤治疗的新型候选药物。