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 fiscal 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 multiple in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings strongly support the translation of combinations of safe and affordable enzyme inhibitors as novel broad-spectrum therapeutics for snakebite.

中文翻译：

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两种小分子毒素抑制剂的组合可提供针对蛇毒蛇咬伤的全大陆临床前功效

蛇咬伤是一种医疗急症，在农村热带社区通常会导致高死亡率和高发病率，而热带社区通常会遇到无法负担得起的治疗方法。蛇毒是造成大多数毒蛇毒的原因，但是毒蛇毒种间的广泛种间差异表明，世界不同地区使用了不同的抗蛇毒毒素治疗方法，这给临床和财政蛇毒咬伤管理带来了挑战。在这里，我们显示了许多经过重新利用的阶段2批准的小分子能够通过抑制不同的酶毒素家族广泛地中和不同的体外蛇毒生物活性。此外，使用多种体内毒化模型，我们证明了由marimastat和varespladib组成的合理选择的双重抑制剂组合的单剂量可预防非洲，南亚和中美洲最重要的毒蛇毒液造成的致死性。我们的发现强烈支持将安全和负担得起的酶抑制剂的组合翻译为蛇咬的新型广谱疗法。