Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections.
Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections.
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DOI：
10.1186/s13071-016-1616-0
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发表时间：
2016-07-01
影响因子：
3.2
通讯作者：
Scandale I
中科院分区：
文献类型：
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作者：
Keiser J;Panic G;Adelfio R;Cowan N;Vargas M;Scandale I
土源性蠕虫（STH）——蛔虫、毛虫和两种钩虫——十二指肠钩虫和美洲钩虫——感染的治疗选择有限，尽管它们给全球健康带来了相当大的负担。本研究的目的是测试公开的 FDA 库针对人类肠道线虫感染实验室模型的活性。所有 1,600 种药物均首先针对锡兰钩虫三期幼虫 (L3) 进行筛选。对活性化合物进行了仔细检查，有毒化合物、仅局部使用的药物以及已经经过充分研究的驱虫药被排除在外。其余的命中化合物在体外对鼠鞭虫第一阶段幼虫 (L1)、Heligmosomoides polygyrus 第三阶段幼虫 (L3) 和三个物种的成虫阶段进行了平行测试。在 H. polygyrus 和 T. muris 小鼠模型中进行了体内研究。在 200 μM 下孵育 72 小时后，测试的 1,600 种化合物中的 54 种显示出针对 A. ceylanicum L3 的活性≥60%（命中率为 3.4%）。十二种化合物进入进一步筛选。成虫 A. ceylanicum 受到的影响最小（1/12 化合物在 50 μM 时有活性），而 12 种测试化合物中的 8 种显示出针对 T. muris L1 (100 μM) 和成虫 (50 μM) 以及 H. polygyrus L3 (200 μM) 的活性。敌百虫是唯一对所有阶段的 A. ceylanicum、H. polygyrus 和 T. muris 都有效的化合物。此外，敌百虫在 T. muris 和 H. polygyrus 小鼠模型中单次口服 200 mg/kg 剂量后，分别实现了 80.1% 和 98.9% 的蠕虫负荷降低。使用小型文库对肠道寄生线虫幼虫阶段进行药物筛选是可行的，并且鉴于针对 STH 感染的药物发现和开发渠道尚空，这一点很重要。不同 STH 物种和阶段的药物活性的差异和共性得到了证实。确定的命中可能作为 STH 药物发现的起点。本文的在线版本 (doi:10.1186/s13071-016-1616-0) 包含补充材料，可供授权用户使用。
Treatment options for infections with soil-transmitted helminths (STH) - Ascaris lumbricoides, Trichuris trichiura and the two hookworm species, Ancylostoma duodenale and Necator americanus - are limited despite their considerable global health burden. The aim of the present study was to test the activity of an openly available FDA library against laboratory models of human intestinal nematode infections. All 1,600 drugs were first screened against Ancylostoma ceylanicum third-stage larvae (L3). Active compounds were scrutinized and toxic compounds, drugs indicated solely for topical use, and already well-studied anthelmintics were excluded. The remaining hit compounds were tested in parallel against Trichuris muris first-stage larvae (L1), Heligmosomoides polygyrus third-stage larvae (L3), and adult stages of the three species in vitro. In vivo studies were performed in the H. polygyrus and T. muris mice models. Fifty-four of the 1,600 compounds tested revealed an activity of > 60 % against A. ceylanicum L3 (hit rate of 3.4 %), following incubation at 200 μM for 72 h. Twelve compounds progressed into further screens. Adult A. ceylanicum were the least affected (1/12 compounds active at 50 μM), while eight of the 12 test compounds revealed activity against T. muris L1 (100 μM) and adults (50 μM), and H. polygyrus L3 (200 μM). Trichlorfon was the only compound active against all stages of A. ceylanicum, H. polygyrus and T. muris. In addition, trichlorfon achieved high worm burden reductions of 80.1 and 98.9 %, following a single oral dose of 200 mg/kg in the T. muris and H. polygyrus mouse model, respectively. Drug screening on the larval stages of intestinal parasitic nematodes is feasible using small libraries and important given the empty drug discovery and development pipeline for STH infections. Differences and commonalities in drug activities across the different STH species and stages were confirmed. Hits identified might serve as a starting point for drug discovery for STH. The online version of this article (doi:10.1186/s13071-016-1616-0) contains supplementary material, which is available to authorized users.