The 3 major classes of soil transmitted helminths (whipworm, hookworm and Ascaris) affect 1.5 billion people worldwide mostly in poor countries, where they have adverse effects on child development, nutrition, and the work capacity of adults. Although there are drugs effective on Ascaris, notably the benzimidazoles, those same drugs show poor efficacy particularly against whipworm (Trichuris trichiura) and to a certain extent hookworm. Parasitic nematodes also infect farm livestock and companion animals. Resistance to currently deployed human and veterinary anthelmintic drugs is a growing problem. Therefore, new chemical anthelmintic lead compounds are urgently needed. One of the fastest routes to a novel therapeutic lead is to screen libraries of drugs which are either already approved for human use or have already been part of clinical trials. We have pursued this approach to anthelmintic lead discovery using an invertebrate automated phenotyping platform (INVAPP) for screening chemicals and the well-established nematode genetic model organism Caenorhabditis elegans. The 400 compound Medicines for Malaria Pandemic Response Box library was screened with each compound tested initially at 1.0 × 10⁻⁴ M. We identified 6 compounds (MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531) active in both an L1-L4 growth / motility assay and in an L4 motility assay. For vorapaxar, an EC₅₀ of 5.7 × 10⁻⁷ M was observed, a value comparable to some commercial anthelmintics. Although not a parasite, the ease with which high-throughput screens can be pursued on the free-living nematode C. elegans makes this a useful approach to identify chemical leads and complement the often lower-throughput experiments on parasitic nematode models.

中文翻译：

---

筛选关于秀丽隐杆线虫的疟疾大流行反应盒化学库的药物确定了重新描述的候选驱虫药物先导物

土壤传播的 3 大类蠕虫（鞭虫、钩虫和蛔虫）影响全球 15 亿人，其中大部分生活在贫困国家，对儿童发育、营养和成年人的工作能力产生不利影响。虽然有一些对蛔虫有效的药物，特别是苯并咪唑类药物，但这些药物的效果很差，尤其是对鞭虫（Trichuris trichiura) 和一定程度的钩虫。寄生线虫也感染农场牲畜和伴侣动物。对目前使用的人类和兽用驱虫药的耐药性是一个日益严重的问题。因此，迫切需要新的化学驱虫先导化合物。获得新型治疗线索的最快途径之一是筛选已经批准用于人类使用或已经进入临床试验的药物库。我们使用无脊椎动物自动表型平台 (INVAPP) 筛选化学品和行之有效的线虫遗传模型生物秀丽隐杆线虫，采用这种方法来发现驱虫铅。筛选了 400 种用于疟疾大流行反应盒的化合物药物库，每种化合物最初以 1.0 × 10 进行测试^-4 M. 我们鉴定了 6 种化合物（MMV1593515（vorapaxar）、MMV102270（联苯胺）、MMV1581032（ABX464）、MMV1580796（rubitecan）、MMV1580505 和 MMV1593531）在 L1-L4 生长/运动试验和 L4 运动试验中均具有活性. 对于vorapaxar，观察到EC ₅₀为5.7 × 10 ^-7 M，该值与一些商业驱虫药相当。虽然不是寄生虫，但可以轻松地在自由生活的线虫C. elegans上进行高通量筛选，这使其成为识别化学先导物和补充寄生线虫模型上通常较低通量的实验的有用方法。