Identification and characterization of the antiplasmodial activity of Hsp90 inhibitors.
Identification and characterization of the antiplasmodial activity of Hsp90 inhibitors.
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DOI：
10.1186/s12936-017-1940-7
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发表时间：
2017-07-19
期刊：
影响因子：
3
通讯作者：
Pizarro JC
中科院分区：
文献类型：
--
作者：
Murillo-Solano C;Dong C;Sanchez CG;Pizarro JC
最近疟疾死亡率的下降正受到东南亚出现的对青蒿素具有耐药性的恶性疟原虫寄生虫的威胁。为了限制耐药寄生虫的影响及其在世界各地的传播，有必要验证抗疟疾药物靶点并确定新的线索，这将作为未来针对疟疾的药物开发规划的基础。为此，对几种Hsp90抑制剂的抗疟原虫潜能进行了表征。因为，Hsp90伴侣蛋白已被认为是对抗包括疟疾在内的多种寄生虫感染的良好药物靶点。在临床试验中被评估为抗癌药物的多种Hsp90抑制剂的化学成分，对疟疾寄生虫进行了测试。在对氯喹敏感和耐药菌株的生长抑制试验中，大多数化合物显示出较强的抗疟原虫活性。化合物体外抗寄生活性与对疟原虫伴侣蛋白的亲和力基本一致。两种最有效的Hsp90抑制剂对两种恶性疟原虫菌株也显示出杀细胞活性。它们的抗疟原虫活性影响疟疾血液循环中的所有寄生虫形式。然而，当与抗疟疾药物（如氯喹或DHA）联合使用时，这种化合物对寄生虫的活性没有显示出协同作用。Hsp90抑制剂的抗寄生活性与其预测靶标恶性疟原虫伴侣蛋白Hsp90的亲和力相关。然而，最有效的化合物也显示出对同源物Grp94的高亲和力。这种关联指出了Hsp90抑制剂的一种作用模式，它将复合疗效与多靶点结合起来。除了它们限制寄生虫复制的能力外，两种化合物也显著影响恶性疟原虫的体外生存能力。最后，结构分析表明，最佳hit代表了一个有希望的支架来开发寄生虫特异性先导物。结果表明，Hsp90抑制剂对疟原虫具有致死性。生物化学和体外数据之间的相关性有力地支持Hsp90作为抗疟原虫的药物靶点。此外，至少有一种Hsp90抑制剂可以作为抗癌治疗药物，作为产生恶性疟原虫特异性先导化合物的起点。本文的在线版本（doi:10.1186/s12936-017-1940-7）包含补充材料，可供授权用户使用。
The recent reduction in mortality due to malaria is being threatened by the appearance of Plasmodium falciparum parasites that are resistant to artemisinin in Southeast Asia. To limit the impact of resistant parasites and their spread across the world, there is a need to validate anti-malarial drug targets and identify new leads that will serve as foundations for future drug development programmes targeting malaria. Towards that end, the antiplasmodial potential of several Hsp90 inhibitors was characterized. Because, the Hsp90 chaperone has been suggested as a good drug target against multiple parasitic infections including malaria. Chemically diverse sets of Hsp90 inhibitors, evaluated in clinical trials as anti-cancer agents, were tested against the malaria parasite. Most of the compounds showed strong antiplasmodial activity in growth inhibition assays against chloroquine sensitive and resistant strains. There was a good agreement between the compound in vitro anti-parasitic activity and their affinity against the Plasmodium chaperone. The two most potent Hsp90 inhibitors also showed cytocidal activity against two P. falciparum strains. Their antiplasmodial activity affected all parasite forms during the malaria blood cycle. However, the compounds activity against the parasite showed no synergy when combined with anti-malarial drugs, like chloroquine or DHA. The Hsp90 inhibitors anti-parasitic activity correlates with their affinity to their predicted target the P. falciparum chaperone Hsp90. However, the most effective compounds also showed high affinity for a close homologue, Grp94. This association points to a mode of action for Hsp90 inhibitors that correlate compound efficacy with multi-target engagement. Besides their ability to limit parasite replication, two compounds also significantly impacted P. falciparum viability in vitro. Finally, a structural analysis suggests that the best hit represents a promising scaffold to develop parasite specific leads according. The results shown that Hsp90 inhibitors are lethal against the malaria parasite. The correlation between biochemical and in vitro data strongly supports Hsp90 as a drug target against the malaria parasite. Furthermore, at least one Hsp90 inhibitor developed as anticancer therapeutics could serve as starting point to generate P. falciparum-specific lead compounds. The online version of this article (doi:10.1186/s12936-017-1940-7) contains supplementary material, which is available to authorized users.
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