New derivatives of benzhydroxamic acid with nematocidal activity target nematode specific C2-domain containing protein A0A6F7Q0A8

Parasitic nematodes cause a wide range of diseases in animals, including humans. However, the efficacy of existing anthelmintic drugs, commonly used to treat these infections, is waning due to the increasing prevalence of drug resistance in nematode populations. This growing challenge underscores the urgent need to discover and develop novel nematocidal drugs that target new molecular pathways. In present study, 13 novel derivatives of benzhydroxamic acid (OMKs) were designed and synthesised. Their anthelmintic activity was tested in the nematodes Haemonchus contortus (barber’s pole worm) and Caenorhabditis elegans (elegant worm) and compared with classical anthelmintics. OMKs´ potential toxicity was assessed in mammalian models. Among others, one compound, designated OMK211, showed the most promising results, as it decreased viability and motility of larval and adult stages of both drug-sensitive and drug-resistant strains of H. contortus, and this was not toxic in mammalians cells in vitro and in mice in vivo. Consequently, thermal proteome profiling analysis was used to infer the molecular target of OMK211 in , H. contortus. The results revealed C2-domain containing protein A0A6F7Q0A8, encoded by gene HCON_00184900, as an interacting partner of OMK211. Using advanced structural prediction and docking tools, this protein is considered an interesting molecular target of new nematocidal drugs as its orthologs are present in several nematodes but not in mammals. In conclusion, novel derivatives of benzhydroxamic acid represent a promising new class of potential anthelmintics with a novel mechanism of action

寄生线虫可在包括人类在内的多种动物中引发多样化疾病。然而，当前常用于治疗此类感染的驱虫药物，其疗效正随着线虫种群耐药性的不断升高而逐渐衰减。这一日益严峻的挑战，凸显出开发靶向全新分子通路的新型杀线虫药物的迫切需求。
本研究设计并合成了13种苯并羟肟酸（benzhydroxamic acid）衍生物（OMKs）。以捻转血矛线虫（Haemonchus contortus，俗称杆状线虫）和秀丽隐杆线虫（Caenorhabditis elegans，俗称秀丽线虫）为测试模型，评估了这些衍生物的驱虫活性，并与经典驱虫药物进行了对照。同时，研究团队在哺乳动物模型中完成了OMKs的潜在毒性评价。
在受试化合物中，编号为OMK211的化合物表现出最具潜力的生物活性：它可降低敏感株与耐药株捻转血矛线虫的幼虫及成虫阶段的存活率与运动能力，且在体外哺乳动物细胞与体内小鼠模型中均未表现出明显毒性。
为此，研究团队采用热蛋白质组谱分析（thermal proteome profiling）技术，对OMK211在捻转血矛线虫中的分子靶点进行了推断。结果显示，由基因HCON_00184900编码的含C2结构域（C2-domain）蛋白A0A6F7Q0A8，是OMK211的相互作用靶点。借助先进的结构预测与分子对接（docking）工具分析可知，该蛋白是极具研究价值的新型杀线虫药物靶点——其直系同源蛋白（orthologs）广泛存在于多种线虫体内，但在哺乳动物中并未发现同源物。
综上，苯并羟肟酸类新型衍生物代表了一类极具前景的潜在新型驱虫药物，其作用机制独具创新性。