Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada.
Department of Biology, Center for Genomics and Systems Biology, New York University, New York, United States.
Elife. 2020 Aug 11;9:e51850. doi: 10.7554/eLife.51850.
The filarial nematode represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria -present in many filariae-which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present DC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of . We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.
丝虫代表了发展中国家主要的致残原因，在近 4000 万人中引发淋巴丝虫病。目前可用的药物并不适合大规模药物管理工作，因此急需新的治疗方法。一个潜在的弱点是内共生细菌——存在于许多丝虫中——对蠕虫至关重要。基于基因组规模的代谢网络已被用于研究原核生物和原生生物，并已被证明在鉴定治疗靶点方面非常有价值，但直到最近才被应用于多细胞真核生物。在这里，我们提出了 DC625，这是第一个寄生虫虫的分区代谢模型。我们使用这个模型来展示代谢途径的使用方式如何使蠕虫适应不同的环境，并预测了一组 102 个对 的生存至关重要的反应。我们用药物测试验证了其中的三个反应，并证明了所有三种化合物都具有新的抗丝虫特性。
