Shanley Harrison T, Taki Aya C, Nguyen Nghi, Wang Tao, Byrne Joseph J, Ang Ching-Seng, Leeming Michael G, Williamson Nicholas, Chang Bill C H, Jabbar Abdul, Sleebs Brad E, Gasser Robin B
Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia.
Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Victoria, 3010, Australia.
Int J Parasitol Drugs Drug Resist. 2024 Aug;25:100534. doi: 10.1016/j.ijpddr.2024.100534. Epub 2024 Mar 19.
Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, designated UMW-9729, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated UMW-9729's potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and the highly pathogenic, blood-feeding Haemonchus contortus (barber's pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested 25 analogues of UMW-9729 for their nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than UMW-9729, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a UMW-9729 analogue, designated 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with UMW-9729; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as possible targets of UMW-9729. Overall, the present study evaluates this anthelmintic candidate and highlights some challenges associated with early anthelmintic investigation.
寄生线虫引起的感染和疾病对全球动物和人类的健康及生产力产生重大不利影响。这些寄生虫的控制通常严重依赖于使用市售化合物（驱虫药）进行治疗。然而，在牲畜中过度或无节制地使用这些化合物已导致与线虫耐药性相关的重大挑战。因此，需要开发具有新型作用机制的新型驱虫药。最近，我们鉴定出一种小分子，命名为UMW - 9729，它对自由生活的模式生物秀丽隐杆线虫具有杀线虫活性。在此，我们在秀丽隐杆线虫和高致病性吸血捻转血矛线虫（捻转胃虫）的构效关系（SAR）研究中评估了UMW - 9729作为驱虫药的潜力，并使用热蛋白质组分析（TPP）探索了化合物 - 靶点关系。首先，我们合成并测试了25种UMW - 9729类似物对捻转血矛线虫（幼虫和成虫）和秀丽隐杆线虫（成虫）的杀线虫活性，为这两个物种建立了初步的杀线虫药效团。我们鉴定出几种对捻转血矛线虫或秀丽隐杆线虫具有显著活性的化合物，其效力比UMW - 9729更高，并发现这两种线虫物种之间化合物生物活性存在显著差异。我们还鉴定出一种UMW - 9729类似物，命名为25，它在体外适度抑制成年雌性捻转血矛线虫的运动。随后，我们推断出三种与UMW - 9729直接相互作用的捻转血矛线虫蛋白（HCON_00134350、HCON_00021470和HCON_00099760）以及五种秀丽隐杆线虫蛋白（F30A10.9、F15B9.8、B0361.6、DNC - 4和UNC - 11）；然而，这两种线虫物种之间没有共享保守的蛋白质靶点。未来的工作旨在扩展对这些及其他寄生线虫物种的SAR研究，并验证在此鉴定出的个别蛋白质作为UMW - 9729可能靶点的情况。总体而言，本研究评估了这种驱虫药候选物，并突出了早期驱虫药研究相关的一些挑战。
