Oxadiazole 2-oxides are toxic to the human hookworm, Ancylostoma ceylanicum, however glutathione reductase is not the primary target.
Oxadiazole 2-oxides are toxic to the human hookworm, Ancylostoma ceylanicum, however glutathione reductase is not the primary target.
复制标题
恶二唑 2-氧化物对人类钩虫（锡兰钩虫）有毒，但谷胱甘肽还原酶不是主要目标。
DOI：
10.1016/j.ijpddr.2012.05.001
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Vermeire,JJ
中科院分区：
文献类型：
--
作者：
Treger,RS;Cook,AG;Rai,G;Maloney,DJ;Simeonov,A;Jadhav,A;Thomas,CJ;Williams,DL;Cappello,M;Vermeire,JJ
Hookworm disease, characterized by severe anemia and cognitive and growth delays, currently affects an estimated 740 million people worldwide. Despite the prevalence of this parasitic disease, few effective drug therapies are in use today, and the heavy reliance upon benzimidazoles highlights the need for the development of novel chemotherapies. Recent work with the trematode parasiteSchistosoma mansonihas identified oxadiazole 2-oxides as effective antischistosomal compounds that function by targeting and inhibiting the antioxidant enzyme, thioredoxin glutathione reductase. In this study, a related enzyme, glutathione reductase, from the human hookwormAncylostoma ceylanicumwas identified and characterized, and itsin vitroactivity in the presence of the oxadiazole 2-oxides was analyzed.Ex vivoworm killing assays were also conducted to establish the relationship between a given compound’s effect upon worm survival and inhibition of recombinant glutathione reductase (rAceGR). Finally, thein vivoanthelminthic efficacy of furoxan (Fx) was assessed in the hamster model of hookworm infection. The predicted amino acid sequence of AceGR contained a prototypical glutathione reductase active site sequence, but no thioredoxin reductase consensus sequences, suggesting that the glutathione and thioredoxin pathways ofA. ceylanicumare distinct. Although 10 of the 42 oxadiazole 2-oxides tested inhibited rAceGR activity by at least 50%, and 15 compounds were toxic to parasitesex vivo, little overlap existed between these two results. We therefore suggest that AceGR is not the primary target of the oxadiazole 2-oxides in effecting parasite death. Lastly, oral treatment ofA. ceylanicuminfected hamsters with furoxan resulted in significantly improved weight gains and reduced intestinal worm burdens compared to vehicle treated controls, supporting continued development of this molecule as a novel anthelminthic.
