Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform.
Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform.
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DOI：
10.3389/fphar.2023.1331224
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发表时间：
2023
影响因子：
5.6
通讯作者：
Casewell, Nicholas R.
中科院分区：
文献类型：
--
作者：
Albulescu, Laura-Oana;Westhorpe, Adam;Clare, Rachel H.;Woodley, Christopher M.;James, Nivya;Kool, Jeroen;Berry, Neil G.;O'Neill, Paul M.;Casewell, Nicholas R.
关键词：
蛇咬伤是一种被忽视的热带疾病，每年造成多达180万人中毒，14万人死亡。为了解决目前抗蛇毒血清存在的治疗局限性，寻找可以作为早期干预措施给予的小分子药物抑制剂最近获得了牵引力。蛇毒是蛋白质、肽和小分子的复杂混合物，其组成在蛇类之间和蛇类内部有很大差异。磷脂酶A2（PLA2）是在医学上重要的毒蛇和眼镜蛇毒液中发现的主要致病毒素类别之一，然而伐瑞拉迪（最初开发用于治疗急性冠状动脉综合征的药物）仍然是唯一显示出在体外和体内有效中和毒液毒性的PLA2抑制剂，导致药物组合极其有限。在这里，我们描述了一个高通量的药物筛选，以确定新的PLA2抑制剂重新利用蛇咬伤的治疗。我们目前的方法优化的384孔板，比色法，高通量筛选测定，允许的吞吐量为每天2002800药物，并报告的筛选后的3003500 I期改造药物库对毒液的罗素蝰蛇，Daboia russelii。我们进一步探索了广谱抑制潜力和有效性，对一系列医学上重要的蛇毒，并证明了我们的方法在确定药物EC50的实用性。总的来说，我们的研究结果支持这种方法在未来的应用，以充分探索化学空间，发现新的PLA2抑制药物的价值，防止严重的病理所造成的蛇咬伤envenoming。
Snakebite envenoming is a neglected tropical disease that causes as many as 1.8 million envenomings and 140,000 deaths annually. To address treatment limitations that exist with current antivenoms, the search for small molecule drug-based inhibitors that can be administered as early interventions has recently gained traction. Snake venoms are complex mixtures of proteins, peptides and small molecules and their composition varies substantially between and within snake species. The phospholipases A2 (PLA2) are one of the main pathogenic toxin classes found in medically important viper and elapid snake venoms, yet varespladib, a drug originally developed for the treatment of acute coronary syndrome, remains the only PLA2 inhibitor shown to effectively neutralise venom toxicity in vitro and in vivo, resulting in an extremely limited drug portfolio. Here, we describe a high-throughput drug screen to identify novel PLA2 inhibitors for repurposing as snakebite treatments. We present method optimisation of a 384-well plate, colorimetric, high-throughput screening assay that allowed for a throughput of ∼2,800 drugs per day, and report on the screening of a ∼3,500 post-phase I repurposed drug library against the venom of the Russell’s viper, Daboia russelii. We further explore the broad-spectrum inhibitory potential and efficacy of the resulting top hits against a range of medically important snake venoms and demonstrate the utility of our method in determining drug EC50s. Collectively, our findings support the future application of this method to fully explore the chemical space to discover novel PLA2-inhibiting drugs of value for preventing severe pathology caused by snakebite envenoming.
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两种小分子毒素抑制剂的治疗组合提供了针对蝰蛇咬伤的广泛临床前疗效。
影响因子：
16.6
作者：
Albulescu LO;Xie C;Ainsworth S;Alsolaiss J;Crittenden E;Dawson CA;Softley R;Bartlett KE;Harrison RA;Kool J;Casewell NR
通讯作者：
Casewell NR
影响因子：
5.1
作者：
Cotrim, Camila Aparecida;Buzzo de Oliveira, Simone Cristina;Toyama, Marcos Hikari
通讯作者：
Toyama, Marcos Hikari
影响因子：
2.8
作者：
Bryan-Quiros, Wendy;Fernandez, Julian;Lomonte, Bruno
通讯作者：
Lomonte, Bruno
影响因子：
2.2
作者：
Bulfone TC;Samuel SP;Bickler PE;Lewin MR
通讯作者：
Lewin MR
影响因子：
6.1
作者：
Cerdá, B;Cerón, JJ;Espín, JC
通讯作者：
Espín, JC