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Trypanosoma cruzi biochemical changes and cell death induced by an organometallic platinum‐based compound
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-06-26 , DOI: 10.1111/cbdd.13332 M. Florencia Mosquillo 1 , Lucía Bilbao 1 , Fabricio Hernández 1 , Florencia Tissot 2 , Dinorah Gambino 3 , Beatriz Garat 1 , Leticia Pérez-Díaz 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-06-26 , DOI: 10.1111/cbdd.13332 M. Florencia Mosquillo 1 , Lucía Bilbao 1 , Fabricio Hernández 1 , Florencia Tissot 2 , Dinorah Gambino 3 , Beatriz Garat 1 , Leticia Pérez-Díaz 1
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Chagas disease is an endemic illness in Latin America caused by the parasite Trypanosoma cruzi. Current chemotherapies are old and inadequate, and the emergence of drug‐resistant strains underscores the need of new drugs. Platinum‐based complexes have been shown to be a promising approach against parasitic diseases. In this work, the effect of 1,1′‐bis(diphenylphosphino)ferrocene pyridine‐2‐thiolate‐1‐oxide Pt(II) hexafluorophosphate, Pt‐dppf‐mpo, was studied on T. cruzi. A promising antitrypanosomal activity was determined for the CL Brener strain with a low cytotoxicity determined using in vitro‐cultured mammal cells. The compound uptake in parasites treated with concentrations of 1× and 10× the IC50 value reached ~75% and 19%, respectively. Pt‐dppf‐mpo induced necrosis after 24 hr of parasite incubation. This event was preceded by depolarization of mitochondrial membrane potential. Cell vitality assays showed high esterase activity in treated parasites. However, despite this increase in metabolic activity, treated epimastigotes showed rounded morphology and loss of flagellum with a reduction in mobility as compound concentration and/or time of incubation was increased. At last, we demonstrate that Pt‐dppf‐mpo incubation also affects the trypomastigote infection process as well as the infection persistence evaluated as the number of amastigotes per cell in a dose‐dependent manner.
中文翻译：
有机金属铂基化合物诱导的克氏锥虫生化变化和细胞死亡
恰加斯病是拉丁美洲的一种地方病，由克鲁斯锥虫引起。当前的化学疗法过时且不足，并且耐药菌株的出现突显了对新药的需求。铂基络合物已被证明是一种抗寄生虫病的有前途的方法。在这项工作中，研究了1,1'-双（二苯基膦基）二茂铁吡啶-2-硫醇盐-1-氧化物Pt（II）六氟磷酸盐Pt-dppf-mpo对克鲁氏锥虫的影响。使用体外培养的哺乳动物细胞，对CL Brener菌株确定了有希望的抗胰蛋白酶活性，且具有较低的细胞毒性。浓度为IC 50的1倍和10倍的寄生虫对化合物的吸收价值分别达到〜75％和19％。寄生虫孵育24小时后，Pt-dppf-mpo引起坏死。此事件之前线粒体膜电位去极化。细胞活力分析表明，在处理过的寄生虫中酯酶活性较高。然而，尽管代谢活性有所提高，但随着化合物浓度和/或温育时间的增加，处理过的鞭mas科动物仍表现出圆形的形态和鞭毛的丧失，并且迁移率降低。最后，我们证明了Pt-dppf-mpo的孵育也会影响锥虫的感染过程，并且感染持久性以剂量依赖性方式评估为每个细胞的变形虫数量。
更新日期：2018-06-26
中文翻译：
有机金属铂基化合物诱导的克氏锥虫生化变化和细胞死亡
恰加斯病是拉丁美洲的一种地方病，由克鲁斯锥虫引起。当前的化学疗法过时且不足，并且耐药菌株的出现突显了对新药的需求。铂基络合物已被证明是一种抗寄生虫病的有前途的方法。在这项工作中，研究了1,1'-双（二苯基膦基）二茂铁吡啶-2-硫醇盐-1-氧化物Pt（II）六氟磷酸盐Pt-dppf-mpo对克鲁氏锥虫的影响。使用体外培养的哺乳动物细胞，对CL Brener菌株确定了有希望的抗胰蛋白酶活性，且具有较低的细胞毒性。浓度为IC 50的1倍和10倍的寄生虫对化合物的吸收价值分别达到〜75％和19％。寄生虫孵育24小时后，Pt-dppf-mpo引起坏死。此事件之前线粒体膜电位去极化。细胞活力分析表明，在处理过的寄生虫中酯酶活性较高。然而，尽管代谢活性有所提高，但随着化合物浓度和/或温育时间的增加，处理过的鞭mas科动物仍表现出圆形的形态和鞭毛的丧失，并且迁移率降低。最后，我们证明了Pt-dppf-mpo的孵育也会影响锥虫的感染过程，并且感染持久性以剂量依赖性方式评估为每个细胞的变形虫数量。
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