Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity.
Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity.
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DOI：
10.2147/ijn.s27540
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发表时间：
2012
影响因子：
8
通讯作者：
Ho CM
中科院分区：
文献类型：
--
作者：
Ding X;Sanchez DJ;Shahangian A;Al-Shyoukh I;Cheng G;Ho CM
传染病导致细胞信号网络内的许多分子组装和通路功能异常。治疗复杂、患病的细胞网络的最有效方法是应用多种药物从多个方面解决问题。然而，确定特定剂量下几种药物的最佳组合以达到终点目标是一项艰巨的任务。在本研究中，我们应用实验反馈系统控制 (FSC) 方法，仅测试了不到 0.1% 的可能药物组合，即可快速确定抑制单纯疱疹病毒 1 感染的最佳药物组合。以抗病毒功效为标准，FSC 迅速确定了一种高效的药物混合物。这种鸡尾酒含有高剂量的利巴韦林。利巴韦林虽然是一种有效的抗病毒药物，但通常会引起治疗药物组合中不希望出现的毒副作用。为了筛选毒性较小的药物组合，我们应用了第二次 FSC 级联搜索，并使用高抗病毒功效和低毒性作为标准。令人惊讶的是，新的药物组合消除了对利巴韦林的需求，但仍然阻止了近 100% 的病例的病毒感染。这种级联搜索为快速发现满足多个标准的新药物组合提供了一个多功能平台。
Infectious diseases cause many molecular assemblies and pathways within cellular signaling networks to function aberrantly. The most effective way to treat complex, diseased cellular networks is to apply multiple drugs that attack the problem from many fronts. However, determining the optimal combination of several drugs at specific dosages to reach an endpoint objective is a daunting task. In this study, we applied an experimental feedback system control (FSC) method and rapidly identified optimal drug combinations that inhibit herpes simplex virus-1 infection, by only testing less than 0.1% of the total possible drug combinations. Using antiviral efficacy as the criterion, FSC quickly identified a highly efficacious drug cocktail. This cocktail contained high dose ribavirin. Ribavirin, while being an effective antiviral drug, often induces toxic side effects that are not desirable in a therapeutic drug combination. To screen for less toxic drug combinations, we applied a second FSC search in cascade and used both high antiviral efficacy and low toxicity as criteria. Surprisingly, the new drug combination eliminated the need for ribavirin, but still blocked viral infection in nearly 100% of cases. This cascade search provides a versatile platform for rapid discovery of new drug combinations that satisfy multiple criteria.