A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes
A Repurposing Strategy for Hsp90 Inhibitors Demonstrates Their Potency against Filarial Nematodes
复制标题
DOI：
10.1371/journal.pntd.0002699
复制
发表时间：
2014-02-01
影响因子：
3.8
通讯作者：
Devaney, Eileen
中科院分区：
文献类型：
--
作者：
Gillan, Victoria;O'Neill, Kerry;Devaney, Eileen
需要新的药物来消除蠕虫引起的感染，因为最常用的药物主要针对微丝蚴或这些感染的第一阶段幼虫。先前在体外进行的研究已经表明，抑制Hsp 90可以杀死巴汉丝虫成虫。由于许多小分子Hsp 90抑制剂已被开发用于癌症化疗，我们测试了几种新的Hsp 90抑制剂的活性，在荧光偏振测定和对微丝蚴和成虫的丝虫在体外。来自所有三种测定的结果相当好地相关，并且一种特定化合物NVP-AUY 922显示出特别的活性，在暴露于药物6天后以低至5.0纳摩尔的浓度抑制来自雌性蠕虫的Mf输出。NVP-AUY 922在短时间暴露于药物24小时后对蠕虫也有活性。基于这些体外数据，NVP-AUY 922在小鼠模型中进行了体内测试，并显示出显著降低蠕虫和微丝蚴的回收率。这些研究提供的原则证明，目前可用的热休克蛋白90抑制剂的再利用可能有潜力开发新的药物与macrofilaricidal properties.Author摘要成年蠕虫是长寿的线虫寄生虫，已被证明很难杀死与现有的药物。目前控制或消除这些寄生虫的活动主要是基于用药物如乙胺嗪或伊维菌素治疗，这些药物优先杀死寄生虫的第一阶段幼虫，即微丝蚴。由于微丝蚴从未受影响的成虫重新填充身体，因此在蠕虫的长生殖寿命期间需要重复给予这些药物。具有杀巨丝虫活性的化合物的可用性将有助于实现控制丝虫感染的目标。Hsp 90是肿瘤细胞中公认的靶标：因此许多肿瘤学项目已经开发了Hsp 90的小分子抑制剂，其中几种是可商购的。在这里，我们提供的原则证明，抑制热休克蛋白90是致命的成虫在体内，以及在体外，这表明这些化合物可能有潜力进一步发展为杀微丝蚴药物。
Novel drugs are required for the elimination of infections caused by filarial worms, as most commonly used drugs largely target the microfilariae or first stage larvae of these infections. Previous studies, conducted in vitro, have shown that inhibition of Hsp90 kills adult Brugia pahangi. As numerous small molecule inhibitors of Hsp90 have been developed for use in cancer chemotherapy, we tested the activity of several novel Hsp90 inhibitors in a fluorescence polarization assay and against microfilariae and adult worms of Brugia in vitro. The results from all three assays correlated reasonably well and one particular compound, NVP-AUY922, was shown to be particularly active, inhibiting Mf output from female worms at concentrations as low as 5.0 nanomolar after 6 days exposure to drug. NVP-AUY922 was also active on adult worms after a short 24 h exposure to drug. Based on these in vitro data, NVP-AUY922 was tested in vivo in a mouse model and was shown to significantly reduce the recovery of both adult worms and microfilariae. These studies provide proof of principle that the repurposing of currently available Hsp90 inhibitors may have potential for the development of novel agents with macrofilaricidal properties.Author Summary Adult filarial worms are long-lived nematode parasites that have proved very difficult to kill with existing drugs. Current campaigns for the control or elimination of these parasites are largely based on treatment with drugs such as diethylcarbamazine or ivermectin, that preferentially kill the first stage larvae of the parasite, the microfilariae. As microfilariae repopulate the body from unaffected adult worms, repeated dosing with these drugs is required over the long reproductive life span of the worm. The availability of compounds with macrofilaricidal activity would help facilitate the goal of controlling filarial infections. Hsp90 is a recognized target in tumor cells: consequently many oncology programs have developed small molecule inhibitors of Hsp90, several of which are commercially available. Here we provide proof of principle that inhibition of Hsp90 is lethal to adult Brugia worms in vivo, as well as in vitro, suggesting that these compounds may have potential for further development as macrofilaricidal drugs.