Inhibition of Tapeworm Thioredoxin and Glutathione Pathways by an Oxadiazole N-Oxide Leads to Reduced Mesocestoides vogae Infection Burden in Mice.
Inhibition of Tapeworm Thioredoxin and Glutathione Pathways by an Oxadiazole N-Oxide Leads to Reduced Mesocestoides vogae Infection Burden in Mice.
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DOI：
10.3390/molecules200711793
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发表时间：
2015-06-26
期刊：
影响因子：
--
通讯作者：
Salinas G
中科院分区：
文献类型：
--
作者：
Pasquet V;Bisio H;López GV;Romanelli-Cedrez L;Bonilla M;Saldaña J;Salinas G
寄生性扁形虫引起严重的传染病，影响世界广大地区的人类和牲畜，但几乎没有有效的药物来治疗它们。硫氧还蛋白谷胱甘肽还原酶（TGR）是维持扁形虫体内氧化还原平衡的重要酶，也是一个很有前途的药理学靶点。我们纯化至均一并表征来自绦虫Mesocestoides vogae（syn. M. corti）。这种纯化揭示了常规TR和GR的情况下。纯化的TGR的谷胱甘肽还原酶活性表现出典型的扁形虫TGR的滞后行为。Consistent，M. vogae基因组分析揭示了含硒半胱氨酸的TGR的存在和常规TR和GR的缺乏。vogae硫氧还蛋白和谷胱甘肽还原酶活性被3，4-双（苯磺酰基）-1，2，5-恶二唑N2-氧化物（VL 16 E）抑制，该恶二唑N-氧化物先前被鉴定为吸虫和绦虫TGRs的抑制剂。最后，我们发现实验感染M.与载体处理的小鼠相比，用吡喹酮（用于扁形虫感染的参考药物）或VL 16 E处理的vogae tetrapidia小鼠表现出腹膜内幼虫数量减少28%。我们的研究结果表明，恶二唑N-氧化物是一个有前途的化学型在体内，并突出了方便的M。vogae作为体内绦虫感染快速评估的模型。
Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising pharmacological target. We purified to homogeneity and characterized the TGR from the tapeworm Mesocestoides vogae (syn. M. corti). This purification revealed absence of conventional TR and GR. The glutathione reductase activity of the purified TGR exhibits a hysteretic behavior typical of flatworm TGRs. Consistently, M. vogae genome analysis revealed the presence of a selenocysteine-containing TGR and absence of conventional TR and GR. M. vogae thioredoxin and glutathione reductase activities were inhibited by 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole N2-oxide (VL16E), an oxadiazole N-oxide previously identified as an inhibitor of fluke and tapeworm TGRs. Finally, we show that mice experimentally infected with M. vogae tetrathyridia and treated with either praziquantel, the reference drug for flatworm infections, or VL16E exhibited a 28% reduction of intraperitoneal larvae numbers compared to vehicle treated mice. Our results show that oxadiazole N-oxide is a promising chemotype in vivo and highlights the convenience of M. vogae as a model for rapid assessment of tapeworm infections in vivo.
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