Mamede Lúcia, Fall Fanta, Vast Madeline, Hughes Kristelle, Martelli Giorgia, Caligiore Francesco, Govaerts Bernadette, Michels Paul A M, Frédérich Michel, Quetin-Leclercq Joëlle
Pharmacognosy Research Group, Louvain Drug Research Institute (LDRI), UCLouvain, Brussels, Belgium; Laboratory of Pharmacognosy, Center of Interdisciplinary Research on Medicines (CIRM), University of Liège, Belgium.
Pharmacognosy Research Group, Louvain Drug Research Institute (LDRI), UCLouvain, Brussels, Belgium.
Int J Parasitol Drugs Drug Resist. 2025 Apr 16;28:100595. doi: 10.1016/j.ijpddr.2025.100595.
Trypanosomiasis is a parasitic disease for which new treatments are needed due to the frequent occurrence of adverse side effects of current available drugs. Natural compounds found in traditionally used plants offer opportunities to discover innovative compounds that could prove pivotal to antitrypanosomal drug development. 3-O-p-(Z/E)-coumaroyltormentic acids (CTA) were isolated first from the West Africa-native tree Vitellaria paradoxa and have demonstrated quite selective in vitro and in vivo antitrypanosomal activity, despite the unknown mode of action. In this study, a metabolomics analysis using the data from both LC-HR-MS and H-NMR described CTA's effects on Trypanosoma brucei after 3 h exposure under 5 or 10 x EC. Our study shows CTA's activity impacted tryptophan metabolism and reveals potential targets in different branches of this metabolism. Our results demonstrate a likely presence of enzymes dedicated to tryptophan, like a tryptophan aminotransferase, tryptophan 2,3-dioxygenase and/or indoleamine 2,3-dioxygenase, and other enzymes of the kynurenine pathway, despite the absence of their description thus far in this species. These data further implicate that CTA's toxic effect on the tryptophan metabolism may be attributed to the decrease of the intracellular level of essential aspartate, resulting from inhibition of its aminotransferase. In resume, our study shines light on the likelihood of the tryptophan metabolism pathway presenting innovative targets toward the development of antitrypanosomal drugs. These require confirmation through functional and enzymatic studies.
锥虫病是一种寄生虫病，由于现有药物频繁出现不良副作用，因此需要新的治疗方法。传统使用植物中发现的天然化合物为发现创新化合物提供了机会，这些化合物可能被证明是抗锥虫药物开发的关键。3-O-p-(Z/E)-香豆酰 tormentic 酸（CTA）最初是从西非本土树木奇异果中分离出来的，尽管其作用方式尚不清楚，但已证明具有相当选择性的体外和体内抗锥虫活性。在这项研究中，使用 LC-HR-MS 和 H-NMR 数据进行的代谢组学分析描述了 CTA 在 5 或 10 倍 EC 浓度下暴露 3 小时后对布氏锥虫的影响。我们的研究表明 CTA 的活性影响色氨酸代谢，并揭示了该代谢不同分支中的潜在靶点。我们的结果表明可能存在专门用于色氨酸的酶，如色氨酸转氨酶、色氨酸 2,3-双加氧酶和/或吲哚胺 2,3-双加氧酶，以及犬尿氨酸途径的其他酶，尽管目前在该物种中尚未对它们进行描述。这些数据进一步表明，CTA 对色氨酸代谢的毒性作用可能归因于其转氨酶受到抑制，导致必需天冬氨酸的细胞内水平降低。总之，我们的研究揭示了色氨酸代谢途径为抗锥虫药物开发提供创新靶点的可能性。这些需要通过功能和酶学研究来证实。
