Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation.
Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation.
复制标题
鉴定通过抑制翻译起始来阻止锥虫生长的双取代脲。
DOI：
10.1038/s41598-018-23259-9
复制
发表时间：
2018
影响因子：
4.6
通讯作者：
Schenkman,Sergio
中科院分区：
文献类型：
--
作者：
Machado,FabricioCastro;Franco,CaioHaddad;DosSantosNeto,JoseVitorino;Dias-Teixeira,KarinaLuiza;Moraes,CarolinaBorsoi;Lopes,UlissesGazos;Aktas,BertalHuseyin;Schenkman,Sergio
一些1，3-二芳基脲和1-((1，4-trans)−4-aryloxycyclohexyl)−3-arylureas(CHAUS)通过真核细胞翻译起始因子2(EIF2)的磷酸化激活血红素调节的激酶，从而抑制哺乳动物癌细胞的蛋白质合成。为了评估这些药物是否有可能通过影响eIF2α亚单位(eIF2α)的磷酸化来抑制锥虫的增殖，我们测试了25个1，3-二芳脲和Chaus的类似物，以对抗恰加斯病的试剂克氏锥虫。其中一种(I-17)对昆虫的复制形式表现出近10倍的选择性，并抑制了Ft的增殖。克鲁兹在哺乳动物细胞内的EC50为1-3 微米，选择性为17倍。I-17还可以在类似剂量下防止非洲锥虫(锥虫、布鲁氏血吸虫和原环状锥虫)的复制。它导致了Thet的变化。核糖体与α结合显著减少，使寄生虫细胞周期停滞在G1期，并促进了eIF2mRNA的磷酸化。这项反对的活动。布鲁氏菌还涉及eIF2α的磷酸化，如用不可磷酸化的eIF2α取代WT-eIF2α，或通过RNAi击倒eIF2蛋白激酶-3，增加了对I-17的抵抗力。因此，我们证明eIF2α的磷酸化通常可以用于开发抑制锥虫的药物，特别是通过干扰eIF2激酶的活性。
Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs againstTrypanosoma cruzi, the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication ofT. cruziinside mammalian cells with an EC50of 1–3 µM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes (Trypanosoma bruceibloodstream and procyclic forms) at similar doses. It caused changes in theT. cruzimorphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity againstT. bruceialso implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases.