Varespladib (LY315920) is a potent and selective inhibitor of group IIA, nonpancreatic secretory PLA2 (sPLA2) with an IC50 value of 9nM [1]. Varespladib acts by binding to the hydrophobic channel of PLA2 toxins and blocking the allosteric activation, which neutralizes the inhibition of prothrombinase by PLA2 toxins[2]. Varespladib has been widely used to delay the symptoms of envenomation and improve survival in a mouse model of lethal snake envenomation [3].
In vitro, Varespladib treatment at 160µM for 12 hours significantly inhibited the Naja atra venom-induced elevation of intracellular reactive oxygen species (ROS) levels and reversed mitochondrial membrane potential damage in NCTC 1469 cells[4]. Varespladib treatment at 10µM for 24h significantly inhibited the mRNA and protein levels of MUC16 in all-trans-retinoic acid (RA)-induced human conjunctival epithelial (HCjE) cells[5]. Preincubation with 26µM Varespladib for 15min significantly inhibited the reduction in twitch amplitude induced by D. siamensis venom and abolished the increase in baseline tension in isolated chicken cervical digastric muscle neuromuscular specimens[6].
In vivo, Varespladib, administered orally at a dose of 50mg/kg daily for 4 weeks, reduced low body weight and abdominal fat, improved gut health and lipid profiles, decreased intestinal inflammation and fibrosis, down-regulated genes involved in immunity and permeability, and suppressed key inflammatory pathways in mice fed a high-fat diet (HFD)[7]. A single dose of Varespladib (4mg/kg) administered via the tail vein for 24 hours reduced levels of rhabdomyolysis and hemolysis markers and ameliorated renal dysfunction in a rat model of wasp sting-induced acute kidney injury[8].
References:
[1] Snyder D W, Bach N J, Dillard R D, et al. Pharmacology of LY315920/S-5920,[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1 H-indol-4-yl] oxy] acetate, a Potent and Selective Secretory Phospholipase A2Inhibitor: A New Class of Anti-Inflammatory Drugs, SPI[J]. The Journal of pharmacology and experimental therapeutics, 1999, 288(3): 1117-1124.
[2] Youngman N J, Walker A, Naude A, et al. Varespladib (LY315920) neutralises phospholipase A2 mediated prothrombinase-inhibition induced by Bitis snake venoms[J]. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 2020, 236: 108818.
[3] Lewin M, Samuel S, Merkel J, et al. Varespladib (LY315920) appears to be a potent, broad-spectrum, inhibitor of snake venom phospholipase A2 and a possible pre-referral treatment for envenomation[J]. Toxins, 2016, 8(9): 248.
[4] Zhao W, Liu J, Wang S, et al. Varespladib mitigates acute liver injury via suppression of excessive mitophagy on Naja atra envenomed mice by inhibiting PLA2[J]. Toxicon, 2024, 242: 107694.
[5] Hori Y, Spurr-Michaud S J, Russo C L, et al. Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16[J]. Investigative ophthalmology & visual science, 2005, 46(11): 4050-4061.
[6] Lay M, Liang Q, Isbister G K, et al. In vitro efficacy of antivenom and varespladib in neutralising Chinese Russell’s viper (Daboia siamensis) venom toxicity[J]. Toxins, 2023, 15(1): 62.
[7] Shirui M, Yuanyuan L, Linfeng W, et al. Varespladib Alleviates Colonic Inflammation Induced by High‐Fat Diet via Downregulating the TGF‐β/Smad Pathway and AA Pathway by Inhibiting sPLA2[J]. Journal of Gastroenterology and Hepatology, 2025, 40(12): 2933-2943.
[8] Wang R, Gao D, Yu F, et al. Phospholipase A2 inhibitor varespladib prevents wasp sting-induced nephrotoxicity in rats[J]. Toxicon, 2022, 215: 69-76.
Varespladib (LY315920)是一种强效、选择性的group IIA, nonpancreatic secretory PLA2 (sPLA2)抑制剂，IC50值为9nM[1]。Varespladib通过结合PLA2毒素的疏水通道并阻断变构激活来发挥作用，从而中和PLA2毒素对凝血酶原酶的抑制效应[2]。Varespladib已被广泛用于延缓毒蛇咬伤症状并提高致死性蛇咬伤小鼠模型的存活率[3]。
在体外，使用160µM的Varespladib处理12小时，显著抑制了Naja atra诱导的NCTC 1469细胞内活性氧（ROS）水平升高，并逆转了线粒体膜电位损伤[4]。使用10µM的Varespladib处理24小时，显著抑制了全反式维甲酸（RA）诱导的人结膜上皮细胞（HCjE）中MUC16的mRNA和蛋白水平[5]。使用26µM的Varespladib预孵育15分钟，显著抑制了D. siamensis蛇毒诱导的鸡颈二腹肌神经肌肉样本的收缩幅度下降，并消除了基线张力的增加[6]。
在体内，每日口服给予50mg/kg剂量的Varespladib，持续4周，减轻了高脂饮食（HFD）喂养小鼠的低体重和腹部脂肪，改善了肠道健康和血脂谱，降低了肠道炎症和纤维化，下调了参与免疫和通透性的基因，并抑制了关键的炎症通路[7]。通过尾静脉单次给予Varespladib（4mg/kg）24小时，降低了黄蜂蜇伤诱导的急性肾损伤大鼠模型中的横纹肌溶解和溶血标志物水平，并改善了肾功能障碍[8]。