Gonzalo Scalese, Ignacio Machado, Fabiana Salazar, E. L. Coitiño, Isabel Correia, J. Pessoa, Leticia Pérez-Díaz, D. Gambino
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Both theoretical predictions and experimental data support the hypothesis that inhibiting the parasite-specific enzyme NADH-fumarate reductase activity plays a crucial role in the trypanocidal action of these complexes. Globally, [VIVO(L-H)(mpo)] complexes could be considered interesting anti-T. cruzi agents that deserve further research.","PeriodicalId":123291,"journal":{"name":"Frontiers in Chemical Biology","volume":" 44","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Facing diseases caused by trypanosomatid parasites: rational design of multifunctional oxidovanadium(IV) complexes with bioactive ligands\",\"authors\":\"Gonzalo Scalese, Ignacio Machado, Fabiana Salazar, E. L. Coitiño, Isabel Correia, J. Pessoa, Leticia Pérez-Díaz, D. 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引用次数: 0
摘要
为了寻找抗击恰加斯病(美洲锥虫病)和利什曼病的新药,我们合成并鉴定了一系列五种杂oleptic钒化合物[VIVO(L-H)(mpo)],其中 L 为 8-羟基喹啉衍生物,mpo 为 2-巯基吡啶 N-氧化物。在固态和溶液中进行了全面的表征。在作为哺乳动物细胞模型的 VERO 细胞上,对这些化合物在克氏锥虫的表原体和胰原体以及在婴儿利什曼原体中的活性进行了评估。这些化合物对两种形式的克鲁兹锥虫和婴儿利什曼原虫都有活性,其中对克鲁兹锥虫感染阶段的敏感性最高。选择性最强的钒化合物[VIVO(L2-H)(mpo)](L2=5-氯-7-碘-8-羟基喹啉)对寄生虫具有充分的选择性,因此被选中进行进一步的深入生物学研究。[VIVO(L2-H)(mpo)]能显著影响细胞衍生的胰原虫的感染潜能,并阻碍克柔子非原虫的复制。研究发现,T. cruzi寄生虫对钒的总摄取量较低,并优先积聚在可溶性蛋白质部分,而在DNA部分的定位几乎可以忽略不计。在不同浓度的化合物中都能观察到杀灭胰病毒的效果。产生氧化应激和诱导线粒体依赖性凋亡被认为是 VIVO 复合物杀死寄生虫的主要机制。理论预测和实验数据都支持这样的假设,即抑制寄生虫特异性酶 NADH-富马酸还原酶的活性在这些复合物的杀锥虫作用中起着至关重要的作用。总的来说,[VIVO(L-H)(mpo)]复合物可被视为有趣的抗克鲁斯绦虫药物,值得进一步研究。
Facing diseases caused by trypanosomatid parasites: rational design of multifunctional oxidovanadium(IV) complexes with bioactive ligands
Searching for new prospective drugs against Chagas disease (American trypanosomiasis) and Leishmaniasis, a series of five heteroleptic vanadium compounds, [VIVO(L-H)(mpo)], where L are 8-hydroxyquinoline derivatives and mpo is 2-mercaptopyridine N-oxide, are synthesized and characterized. Comprehensive characterizations are conducted in solid state and in solution. The compounds are evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi and in promastigotes of Leishmania infantum, alongside on VERO cells, as a mammalian cell model. The compounds exhibit activity against both forms of T. cruzi and promastigotes of L. infantum, with the trypomastigote infective stage of T. cruzi displaying the highest sensitivity. The most selective vanadium compound [VIVO(L2-H)(mpo)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, globally shows adequate selectivity towards the parasite and was selected to carry out further in-depth biological studies. [VIVO(L2-H)(mpo)] significantly impacted the infection potential of cell-derived trypomastigotes and hindered the replication of the T. cruzi amastigote form. Low total vanadium uptake by T. cruzi parasites and preferential accumulation in the soluble proteins fraction, with negligible localization in the DNA fraction, are determined. A trypanocide effect is observed across various concentrations of the compound. The generation of oxidative stress and the induction of mitochondria-dependent apoptosis are proposed as the main mechanisms of the parasite’s death by the VIVO compounds. Both theoretical predictions and experimental data support the hypothesis that inhibiting the parasite-specific enzyme NADH-fumarate reductase activity plays a crucial role in the trypanocidal action of these complexes. Globally, [VIVO(L-H)(mpo)] complexes could be considered interesting anti-T. cruzi agents that deserve further research.