Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC, Australia.
Department of Biochemical Sciences, Charles University, Faculty of Pharmacy, Hradec Králové, Czech Republic.
Parasit Vectors. 2019 Apr 30;12(1):191. doi: 10.1186/s13071-019-3426-7.
Due to anthelmintic resistance problems, there is a need to discover and develop new drugs for the treatment and control of economically important and pathogenic nematodes of livestock animals. With this focus in mind, we screened 236 compounds from a library (called the 'Kurz-box') representing chemically diverse classes such as heterocyclic compounds (e.g. thiazoles, pyrroles, quinolines, pyrimidines, benzo[1,4]diazepines), hydoxamic acid-based metalloenzyme inhibitors, peptidomimetics (bis- and tris-pyrimidoneamides, alkoxyamides) and various intermediates on Haemonchus contortus, one of the most important parasitic nematodes of ruminants.
In the present study, we tested these compounds, and measured the inhibition of larval motility and development of exsheathed third-stage (xL3) and fourth-stage (L4) larvae of H. contortus using an optimised, whole-organism phenotypic screening assay.
Of the 236 compounds, we identified two active compounds (called BLK127 and HBK4) that induced marked phenotypic changes in the worm in vitro. Compound BLK127 induced an 'eviscerated' phenotype in the xL3 stage and also inhibited L4 development. Compound HBK4 exerted a 'curved' phenotype in both xL3s and L4s.
The findings from this study provide a basis for future work on the chemical optimisation of these compounds, on assessing the activity of optimised compounds on adult stages of H. contortus both in vitro and in vivo (in the host animal) and against other parasitic worms of veterinary and medical importance.
由于驱虫剂耐药性问题，需要发现和开发新的药物来治疗和控制对经济重要的家畜致病性线虫。考虑到这一重点，我们从一个代表化学多样性的化合物库（称为“Kurz-box”）中筛选了 236 种化合物，这些化合物包括杂环化合物（如噻唑、吡咯、喹啉、嘧啶、苯并[1,4]二氮杂*）、基于羟肟酸的金属蛋白酶抑制剂、肽模拟物（双和三嘧啶酮酰胺、烷氧基酰胺）和各种中间体，这些化合物针对的是反刍动物中最重要的寄生线虫之一旋毛虫。
在本研究中，我们测试了这些化合物，并使用优化的全生物体表型筛选测定法，测量了幼虫运动抑制和脱去鞘的第三期（xL3）和第四期（L4）幼虫发育的抑制作用。
在 236 种化合物中，我们鉴定出两种活性化合物（称为 BLK127 和 HBK4），它们在体外对线虫引起明显的表型变化。化合物 BLK127 在 xL3 期诱导出“内脏暴露”的表型，同时也抑制 L4 发育。化合物 HBK4 在 xL3 和 L4 中均表现出“弯曲”的表型。
本研究的结果为进一步对这些化合物进行化学优化、评估优化化合物在旋毛虫成虫阶段的体外和体内（在宿主动物中）以及对其他具有兽医和医学重要性的寄生蠕虫的活性提供了基础。
