Departamento de Biofísica e Farmacologia, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Botucatu, SP, Brazil.
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica.
Biochim Biophys Acta Gen Subj. 2021 Jul;1865(7):129913. doi: 10.1016/j.bbagen.2021.129913. Epub 2021 Apr 16.
The treatment for snakebites is early administration of antivenom, which can be highly effective in inhibiting the systemic effects of snake venoms, but is less effective in the treatment of extra-circulatory and local effects. To complement standard-of-care treatments such as antibody-based antivenoms, natural and synthetic small molecules have been proposed for the inhibition of key venom components such as phospholipase A (PLA) and PLA-like toxins. Varespladib (compound LY315920) is a synthetic molecule developed and clinically tested aiming to block inflammatory cascades of several diseases associated with high PLAs. Recent studies have demonstrated this molecule is able to potently inhibit snake venom catalytic PLA and PLA-like toxins.
In vivo and in vitro techniques were used to evaluate the inhibitory effect of varespladib against MjTX-I. X-ray crystallography was used to reveal details of the interaction between these molecules. A new methodology that combines crystallography, mass spectroscopy and phylogenetic data was used to review its primary sequence.
Varespladib was able to inhibit the myotoxic and cytotoxic effects of MjTX-I. Structural analysis revealed a particular inhibitory mechanism of MjTX-I when compared to other PLA-like myotoxin, presenting an oligomeric-independent function.
Results suggest the effectiveness of varespladib for the inhibition of MjTX-I, in similarity with other PLA and PLA-like toxins.
Varespladib appears to be a promissory molecule in the treatment of local effects led by PLA and PLA-like toxins (oligomeric dependent and independent), indicating that this is a multifunctional or broadly specific inhibitor for different toxins within this superfamily.
蛇伤的治疗方法是早期使用抗蛇毒血清，它可以有效地抑制蛇毒的全身作用，但对循环外和局部作用的治疗效果较差。为了补充基于抗体的抗蛇毒血清等标准治疗方法，已经提出了天然和合成小分子，用于抑制磷脂酶 A（PLA）和 PLA 样毒素等关键毒液成分。Varespladib（化合物 LY315920）是一种合成分子，旨在阻断与高 PLA 相关的几种疾病的炎症级联反应，已被开发并在临床上进行了测试。最近的研究表明，这种分子能够有效地抑制蛇毒催化 PLA 和 PLA 样毒素。
使用体内和体外技术来评估 varespladib 对 MjTX-I 的抑制作用。X 射线晶体学用于揭示这些分子之间相互作用的细节。一种新的结合晶体学、质谱和系统发育数据的方法用于审查其一级序列。
Varespladib 能够抑制 MjTX-I 的肌毒性和细胞毒性作用。结构分析表明，与其他 PLA 样肌毒素相比，MjTX-I 具有特定的抑制机制，呈现出寡聚体非依赖性功能。
结果表明，varespladib 对 MjTX-I 的抑制作用有效，与其他 PLA 和 PLA 样毒素相似。
Varespladib 似乎是一种有前途的分子，可用于治疗由 PLA 和 PLA 样毒素（寡聚体依赖和非依赖）引起的局部作用，表明这是针对该超家族中不同毒素的多功能或广泛特异性抑制剂。
