Oral activity of the antimalarial endoperoxide 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Leishmania donovani complex
Oral activity of the antimalarial endoperoxide 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Leishmania donovani complex
复制标题
DOI：
10.1371/journal.pntd.0007235
复制
发表时间：
2019-03-01
影响因子：
3.8
通讯作者：
Iwanaga, Shiroh
中科院分区：
文献类型：
--
作者：
Kwofie, Kofi Dadzie;Sato, Kai;Iwanaga, Shiroh
内脏利什曼病（VL）是世界范围内的一个主要问题，引起严重的发病率和死亡率。现有的抗VL药物有局限性，包括它们的侵入性给药方法，治疗方案的持续时间长。此外，还存在治疗复发增加以及使用米替福辛（VL的唯一口服药物）发现耐药临床菌株的问题。因此，迫切需要新的替代口服药物治疗VL。在目前的研究中，我们展示了一种新型口服抗疟疾内过氧化物N-251的利什曼尼效应。在我们的体外研究中，N-251选择性和特异性杀死多诺瓦利什曼原虫D10无尾线虫，对宿主细胞无毒性。此外，N-251对L. donovani D10和其他L. donovani复合体寄生虫的原鞭毛菌活性相当，表明其具有广泛的活性谱。此外，即使在小鼠体内建立了进行性感染后，口服N-251也能显著消除无尾线虫。最后，N-251通过寄生虫死亡抑制小鼠肝脏肉芽肿的形成。这些结果表明，N-251作为口服药物具有良好的治疗效果，因此，N-251有望成为开发新的口服化疗药物的先导化合物。
Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.