An approach to the development of new drugs for African trypanosomiasis.
An approach to the development of new drugs for African trypanosomiasis.
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DOI：
10.1084/jem.148.2.569
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发表时间：
1978-08-01
期刊：
影响因子：
--
通讯作者：
Cerami A
中科院分区：
文献类型：
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作者：
Meshnick SR;Blobstein SH;Grady RW;Cerami A
血流形式的布氏锥虫布氏锥虫不能分解过氧化氢，这构成了我们试图开发新的药理学试剂来杀死这些生物体的基础。这些寄生虫消耗的氧气中约有1-3%以过氧化氢的形式出现。我们以前的观察，自由基引发剂，如血红素和血卟啉D证明是锥虫在体外和体内，分别，促使这类化合物的作用机制，以提高其治疗效果的调查。使用无细胞匀浆检查锥虫内H2 O2产生的位点。本文所述的实验表明，H2 O2是由α-甘油磷酸脱氢酶以外源方式形成的，并且生物体中不存在处理这种潜在毒性化合物的酶促方法。萘醌被发现显着增加速率的耗氧量和H2 O2生产锥虫线粒体制剂。据推测，萘醌是作为辅酶Q类似物。添加亚裂解浓度的萘醌和血红素导致体外生物体的协同裂解。增加T. B.布氏杆菌对自由基损伤的影响包括细胞内谷胱甘肽浓度的降低。这是通过使用杀锥虫的砷剂来实现的。三氧化二砷和血红素在体外协同作用，通过加入萘醌进一步增强的效果。此外，血卟啉D和扑热息痛对T。B.布鲁氏菌感染的小鼠。
The inability of the bloodstream form of Trypanosoma brucei brucei to decompose hydrogen peroxide forms the basis of our attempt to develop new pharmacological agents to kill these organisms. Approximately 1-3% of the oxygen consumed by these parasites appears in the form of hydrogen peroxide. Our previous observation that free radical initiators such as heme and hematoporphyrin D proved to be trypanocidal in vitro and in vivo, respectively, prompted this investigation into the mechanism of action of this class of compounds to enhance their therapeutic efficacy. The locus of H2O2 production within the trypanosome was examined using cell-free homogenates. Experiments described herein suggest that H2O2 is formed by the alpha-glycerol phosphate dehydrogenase in an adventitious manner, and that no enzymatic means of disposing of this potentially toxic compound are present with the organisms. Naphthoquinones were found to substantially increase the rate of both oxygen consumption and H2O2 production by trypanosomal mitochondrial preparations. Presumably, the naphthoquinones are acting as coenzyme Q analogues. The addition of sublytic concentrations of both naphthoquinones and heme leads to a synergistic lysis of the organisms in vitro. Another approach to increasing the susceptibility of T. b. brucei to free radical damage involved reduction of the intracellular concentration of glutathione. This was accomplished through the use of trypanocidal arsenicals. Melarsenoxide and heme acted synergistically in vitro, an effect which was further enhanced via addition of a naphthoquinone. Moreover, hematoporphyrin D and tryparsamide were shown to have a synergistic effect in T. b. brucei-infected mice.