Keiser Jennifer, Panic Gordana, Adelfio Roberto, Cowan Noemi, Vargas Mireille, Scandale Ivan
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
University of Basel, Basel, Switzerland.
Parasit Vectors. 2016 Jul 1;9(1):376. doi: 10.1186/s13071-016-1616-0.
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.
尽管土壤传播的蠕虫（STH）——蛔虫、鞭虫以及两种钩虫（十二指肠钩虫和美洲板口线虫）感染给全球健康带来了相当大的负担，但其治疗选择仍然有限。本研究的目的是测试一个公开可用的美国食品药品监督管理局（FDA）药物库对人类肠道线虫感染实验室模型的活性。
首先针对锡兰钩虫第三期幼虫（L3）对所有1600种药物进行筛选。对活性化合物进行仔细审查，并排除有毒化合物、仅用于局部使用的药物以及已被充分研究的驱虫药。将剩余的有活性化合物同时针对鼠鞭虫第一期幼虫（L1）、多房棘球绦虫第三期幼虫（L3）以及这三种物种的成虫期进行体外测试。在多房棘球绦虫和鼠鞭虫小鼠模型中进行体内研究。
在200μM浓度下孵育72小时后，所测试的1600种化合物中有54种对锡兰钩虫L3显示出>60%的活性（命中率为3.4%）。12种化合物进入进一步筛选。成年锡兰钩虫受影响最小（1/12种化合物在50μM时有活性），而12种测试化合物中有8种对鼠鞭虫L1（100μM）和成虫（50μM）以及多房棘球绦虫L3（200μM）显示出活性。敌百虫是唯一对锡兰钩虫、多房棘球绦虫和鼠鞭虫所有阶段均有活性的化合物。此外，在鼠鞭虫和多房棘球绦虫小鼠模型中，分别单次口服200mg/kg敌百虫后，蠕虫负荷分别显著降低了80.1%和98.9%。
使用小型药物库对肠道寄生线虫的幼虫阶段进行药物筛选是可行的，鉴于针对土壤传播的蠕虫感染的药物发现和开发渠道空白，这一点很重要。证实了不同土壤传播的蠕虫物种和阶段在药物活性方面的差异和共性。所确定的有活性化合物可能作为土壤传播的蠕虫药物发现的起点。
