Neglected tropical diseases are of growing worldwide concern and schistosomiasis, caused by parasitic flatworms, continues to be a major threat with more than 200 million people requiring preventive treatment. As praziquantel (PZQ) remains the treatment of choice, an urgent need for alternative treatments motivates research to identify new lead compounds that would complement PZQ by filling the therapeutic gaps associated with this treatment. Because impairing parasite neurotransmission remains a core strategy for control of parasitic helminths, we screened a library of 708 compounds with validated biological activity in humans on the blood fluke Schistosoma mansoni, measuring their effect on the motility on schistosomulae and adult worms. The primary phenotypic screen performed on schistosomulae identified 70 compounds that induced changes in viability and/or motility. Screening different concentrations and incubation times identified molecules with fast onset of activity on both life stages at low concentration (1 μM). To complement this study, similar assays were performed with chemical analogs of the cholinomimetic drug arecoline and the calcilytic molecule NPS-2143, two compounds that rapidly inhibited schistosome motility; 17 arecoline and 302 NPS-2143 analogs were tested to enlarge the pool of schistosomicidal molecules. Finally, validated hit compounds were tested on three functionally-validated neuroregulatory S. mansoni G-protein coupled receptors (GPCRs): Sm5HTR (serotonin-sensitive), SmGPR2 (histamine) and SmD2 (dopamine), revealing NPS-2143 and analogs as potent inhibitors of dopamine/epinine responses on both human and S. mansoni GPCRs. This study highlights the potential for repurposing known human therapeutic agents for potential schistosomicidal effects and expands the list of hits for further progression.

被忽视的热带病在世界范围内日益引起关注，由寄生性扁虫引起的血吸虫病仍是主要威胁，有超过2亿人需要预防治疗。由于吡喹酮（PZQ）仍然是首选治疗方法，对替代疗法的迫切需求促使研究人员确定新的先导化合物，以弥补与PZQ相关的治疗空白，从而补充PZQ。由于寄生虫神经传递受损仍然是控制寄生虫蠕虫的一项核心策略，因此我们筛选了在人类血吸虫曼氏血吸虫中已验证的具有人类生物活性的708种化合物的文库，测量它们对血吸虫和成虫蠕虫蠕动的影响。在血吸虫上进行的主要表型筛选确定了70种诱导活力和/或运动性变化的化合物。筛选不同的浓度和孵育时间可鉴定出在低浓度（1μM）的两个生命阶段都具有快速启动活性的分子。为了补充这项研究，用拟胆碱药物槟榔碱和钙分解分子NPS-2143的化学类似物进行了类似的测定，这两种化合物可迅速抑制血吸虫的运动。测试了17种槟榔碱和302 NPS-2143类似物，以扩大血吸虫分子的数量。最后，在三种经过功能验证的神经调节曼氏链球菌上测试了经过验证的命中化合物G蛋白偶联受体（GPCR）：Sm5HTR（5-羟色胺敏感），SmGPR2（组胺）和SmD2（多巴胺），揭示NPS-2143和类似物是对人和曼氏沙门氏菌GPCR的多巴胺/依匹宁反应的有效抑制剂。这项研究强调了重新利用已知的人类治疗剂潜在的血吸虫杀伤作用的潜力，并扩大了进一步发展的研究范围。