Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2
Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2
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DOI：
10.1016/j.toxicon.2018.11.292
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发表时间：
2019-01-01
期刊：
影响因子：
2.8
通讯作者：
Lomonte, Bruno
中科院分区：
文献类型：
--
作者：
Bryan-Quiros, Wendy;Fernandez, Julian;Lomonte, Bruno
需要开发存在于蛇毒中的毒性酶的特异性和临床上有用的抑制剂，所述毒性酶是全球数千名遭受毒液蛰入的人中发生的严重组织损伤和危及生命的作用的原因。LY 315920（伐瑞拉迪，S-5920，A-001）是一种低分子量药物，开发用于抑制几种人分泌型磷脂酶A（2）（PLA（2）s），最近显示也能高效抑制全蛇毒中的PLA（2）s，但尚未研究其对纯化蛇毒PLA（2）s的直接作用。这项工作评估了LY 315920中和结构组I（假毒素）和II（crotoxin B和myotoxin I）的三种分离的PLA（2）毒素及其相应的全毒液的酶活性和毒性活性的能力。在体外，LY 315920抑制了这三种酶在合成底物上的催化活性。该药物还阻断了它们对培养的小鼠肌管的细胞毒性作用。在小鼠中，毒素或毒液与LY 315920预孵育，然后肌肉注射，导致肌肉损伤的显着抑制。最后，立即，独立的注射LY 315920的毒素或毒液接种的网站也导致在一个大的减少肌坏死的情况下，假dexin和myotoxin-I，和Pseudechis coletti和Bothrops asper全毒液，这表明一种可能的方法，在紧急情况下的药物输送。目前的研究结果增加了证据，表明使用LY 315920作为蛇咬伤现场解毒剂的可能性，旨在限制临床环境中许多毒液PLA 2诱导的肌坏死。
A need exists to develop specific and clinically useful inhibitors of toxic enzymes present in snake venoms, responsible for severe tissue damage and life-threatening effects occurring in thousands of people suffering envenomations globally. LY315920 (Varespladib, S-5920, A-001), a low molecular weight drug developed to inhibit several human secreted phospholipases A(2) (PLA(2)s), was recently shown to also inhibit PLA(2)s in whole snake venoms with high potency, yet no studies have examined its direct effect on purified snake venom PLA(2)s. This work evaluated the ability of LY315920 to neutralize the enzymatic and toxic activities of three isolated PLA(2) toxins of structural groups I (pseudexin) and II (crotoxin B and myotoxin I), and their corresponding whole venoms. In vitro, LY315920 inhibited the catalytic activity of these three enzymes upon a synthetic substrate. The drug also blocked their cytotoxic effect on cultured murine myotubes. In mice, preincubation of the toxins or venoms with LY315920, followed by their intramuscular injection, resulted in significant inhibition of muscle damage. Finally, immediate, independent injection of LY315920 at the site of toxin or venom inoculation also resulted in a large reduction of myonecrosis in the case of pseudexin and myotoxin-I, and of Pseudechis colletti and Bothrops asper whole venoms, suggesting a possible method of drug delivery in emergency situations. Present findings add evidence to suggest the possibility of using LY315920 as a field antidote in snakebites, aiming to limit the myonecrosis induced by many venom PLA2s in the clinical setting.