Chua Ming Jang, Arnold Megan S J, Xu Weijun, Lancelot Julien, Lamotte Suzanne, Späth Gerald F, Prina Eric, Pierce Raymond J, Fairlie David P, Skinner-Adams Tina S, Andrews Katherine T
Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, Australia.
Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):42-50. doi: 10.1016/j.ijpddr.2016.12.005. Epub 2016 Dec 23.
Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC 9-370 nM), with belinostat, panobinostat and vorinostat having 8-45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC > 20 μM) or S. mansoni schistosomula (IC > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4-7 and 4-10 after infection (P < 0.05), respectively.
疟疾、血吸虫病和利什曼病是最常见的热带寄生虫病，每种疾病都需要新的创新治疗方法。针对寄生虫的关键途径，如调节基因表达和细胞周期进程的途径，是发现新药先导物的关键策略。在本研究中，检测了四种临床批准的靶向组蛋白/赖氨酸脱乙酰酶的抗癌药物（伏立诺他、贝利司他、帕比司他和罗米地辛）对诺氏疟原虫、曼氏血吸虫、亚马逊利什曼原虫和杜氏利什曼原虫的体外活性，并检测了其中两种药物在小鼠疟疾模型中的体内活性。所有四种化合物都是诺氏疟原虫的有效抑制剂（IC9 - 370 nM），贝利司他、帕比司他和伏立诺他对寄生虫的选择性是人新生儿包皮成纤维细胞（NFF）或人胚肾（HEK 293）细胞的8 - 45倍，而罗米地辛没有选择性。每种HDAC抑制剂药物都导致诺氏疟原虫组蛋白H4的高乙酰化。这些药物对利什曼原虫无鞭毛体或前鞭毛体寄生虫（IC>20 μM）或曼氏血吸虫童虫（IC>10 μM）均无活性，然而罗米地辛抑制曼氏血吸虫成虫交配和产卵（IC ∼10 μM）。口服伏立诺他或帕比司他（25 mg/kg，每日两次，共四天）的伯氏疟原虫感染小鼠中观察到适度的体内活性，分别在感染后第4 - 7天和第4 - 10天观察到寄生虫血症显著降低（P<0.05）。
