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Abstract：
Trypanosoma cruzi, the causal agent of Chagas disease, has peroxiredoxins (PRXs) expressed in all stages of the parasite and whose function is to detoxify oxidizing agents, such as reactive oxygen species (ROS). These proteins are central for the survival and replication of the parasite and have been proposed as virulence factors. Because of their importance, they have also been considered as possible therapeutic targets, although there is no specific drug against them. One of them, the mitochondrial PRX (TcMPX), is important in the detoxification of ROS in this organelle and has a role in the infectivity of T. cruzi. However, their structural characteristics are unknown, and possible inhibitors have not been proposed. The aim was to describe in detail some structural characteristics of TcMPX and compare it with several PRXs to find possible similarities and repositioning the antibiotic Thiostrepton as a potential inhibitor molecule. It was found that, in addition to the characteristic active site of a 2-cys PRX, this protein has a possible transmembrane motif and motifs involved in resistance to hyper oxidation. The homology model suggests a high structural similarity with human PRX3. This similarity was corroborated by cross-recognition using an anti-human PRX antibody. In addition, molecular docking showed that Thiostrepton, a potent inhibitor of human PRX3, could bind to TcMPX and affect its function. Our results show that Thiostrepton reduces the proliferation of T. cruzi epimastigotes, cell-derived trypomastigotes, and blood trypomastigotes with low cytotoxicity on Vero cells. We also demonstrated a synergic effect of Thriostepton and Beznidazol. The convenience of seeking treatment alternatives against T. cruzi by repositioning compounds as Thiostrepton is discussed.
摘要：
克氏锥虫,查加斯病的病因,具有在寄生虫的所有阶段表达的过氧化物酶（PRX），其功能是使氧化剂解毒，例如活性氧(ROS)。这些蛋白质对于寄生虫的存活和复制至关重要，并已被提出作为毒力因子。因为它们的重要性,它们也被认为是可能的治疗靶点，尽管没有针对它们的特定药物。其中一个,线粒体PRX（TcMPX），在该细胞器中ROS的解毒中很重要，并且在T.cruzi的感染性中起作用。然而,它们的结构特征未知，和可能的抑制剂尚未提出。目的是详细描述TcMPX的一些结构特征，并将其与几种PRX进行比较，以发现可能的相似性，并将抗生素Thiostrepton重新定位为潜在的抑制剂分子。结果发现,除了2-cysPRX的特征性活性位点，这种蛋白质可能具有跨膜基序和与抗氧化有关的基序。同源性模型表明与人PRX3具有高度的结构相似性。这种相似性通过使用抗人PRX抗体的交叉识别得到证实。此外,分子对接表明，一种有效的人PRX3抑制剂，可以与TcMPX结合并影响其功能。我们的结果表明，硫链菌素减少了T.cruziepimastigotes的增殖，细胞来源的色素动物，和对Vero细胞具有低细胞毒性的血液锥虫。我们还证明了Thriosteppton和Beznidazol的协同作用。讨论了通过将化合物重新定位为Thiostrepton来寻求针对T.cruzi的治疗方法的便利性。
