A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite.
A therapeutic combination of two small molecule toxin inhibitors provides broad preclinical efficacy against viper snakebite.
复制标题
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。
DOI：
10.1038/s41467-020-19981-6
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发表时间：
2020-12-15
影响因子：
16.6
通讯作者：
Casewell NR
中科院分区：
文献类型：
--
作者：
Albulescu LO;Xie C;Ainsworth S;Alsolaiss J;Crittenden E;Dawson CA;Softley R;Bartlett KE;Harrison RA;Kool J;Casewell NR
蛇咬伤是一种医疗紧急情况，在热带农村社区造成高死亡率和发病率，通常会延迟获得负担不起的治疗。蝰蛇是大多数蛇毒的罪魁祸首，但毒液成分的广泛种间差异决定了世界不同地区使用不同的抗蛇毒血清治疗，导致临床和金融蛇咬伤管理挑战。在这里，我们表明，一些重新利用的第2阶段批准的小分子能够通过抑制不同的酶毒素家族在体外广泛中和不同的蝰蛇毒液生物活性。此外，使用小鼠体内毒液中毒模型，我们证明了单次剂量的合理选择的由马立马司他和伐瑞拉迪组成的双重抑制剂组合可预防由非洲、南亚和中美洲最具医学重要性的毒蛇的毒液引起的小鼠致死性。我们的研究结果支持翻译的组合重新利用小分子为基础的毒素抑制剂作为蛇咬伤的广谱治疗。蛇咬伤是一种危及生命的被忽视的热带疾病，目前使用不同的基于抗体的抗蛇毒血清进行治疗，每种抗蛇毒血清对特定蛇种的咬伤有效，但对其他蛇种无效。在这里，作者表明，两种毒素抑制再利用药物的组合为实验动物提供了广泛的保护，使其免受多种蛇类咬伤的致命影响。
Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and financial snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using murine in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents murine lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings support the translation of combinations of repurposed small molecule-based toxin inhibitors as broad-spectrum therapeutics for snakebite. Snakebite is a life-threatening neglected tropical disease that is currently treated using different antibody-based antivenoms, each effective against bites of specific snake species, but not others. Here, the authors show that a combination of two toxin-inhibiting repurposed drugs provides broad protection in experimental animals against the lethal effects of snakebites from multiple snake species.
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影响因子：
2.8
作者：
Alape-Giron, Alberto;Flores-Diaz, Marietta;Calvete, Juan J.
通讯作者：
Calvete, Juan J.
影响因子：
2.3
作者：
Kumar, K. G. Sajeeth;Narayanan, Santhosh;Thulaseedharan, N. K.
通讯作者：
Thulaseedharan, N. K.
影响因子：
3
作者：
Kim, Hyo Shik;Lee, Kyung Eun;Oh, Ji Hyun;Jung, Chan Sung;Choi, Dughyun;Kim, Yunsuek;Jeon, Jin Seok;Han, Dong Cheol;Noh, Hyunjin
通讯作者：
Noh, Hyunjin
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：
81.5
作者：
Gutierrez, Jose Maria;Calvete, Juan J.;Warrell, David A.
通讯作者：
Warrell, David A.